WO2019180176A1 - Composition for the treatment of schizophrenia and/or psychosis - Google Patents

Abstract

Schizophrenia is a serious disease affecting one percent of the entire global population. Even though the detrimental effects of Schizophrenia on the individual and society at large are known and well documented, it is commonly agreed in the medical community that one of the main unmet needs in the treatment of Schizophrenia is a composition which can treat cognition impairment while also preventing or treating Schizophrenia-triggered psychosis. The present invention provides compositions and agents for addressing this unmet need. In particular, the agents are 5-HT3R and/or 5-HT6R antagonists.

Description

Composition for the treatment of schizophrenia and/or psychosis

Technical field

The present invention is encompassed within the field of psychotherapeutics and provides a novel therapy for the treatment and/or prevention of psychosis and/or schizophrenia.

Background art

Schizophrenia is a serious disease affecting one percent of the entire global population including about three million Americans. The annual cost of this disorder to the United Sates alone due to loss of employment, hospitalizations, medications, and the like exceeds 60 billion dollars annually and its toll in human suffering is shown by the ten to thirteen percent suicide rate for people who have the disease (American Psychiatric Association Public Information Online [1998] http://www.psych.org).

Schizophrenia is a chronic, severe mental disorder characterized by positive symptoms (including delusions, hallucinations and disordered thought), negative symptoms (such as apathy, poverty of speech and lack of interest in social interactions) and cognitive dysfunction (Tandon et al 2013, Schizophr Res. 150: 3-10; Leucht et al.2007 Acta Psychiatr Scand. 116: 317-333). A long history of research has demonstrated the efficacy of D2 receptor antagonism in the alleviation of positive and disorganized symptoms (Gray, 1998. Schizophrenia Bull. 24(2): 249-266). Persistence of negative symptoms often continues, even following neuroleptic treatment (Arndt et al., 1995. Arch Gen Psychiatry. 52:352-359). The stability of negative symptoms and cognition has been, by some, attributed to the neuroleptic medications themselves (Carpenter, 1997. Schizophrenia Bull. 23(1): 11 - 18); Hill et al., 2009. Expert Rev Neurother. 10(1 ):43-57). Current unmet needs in the treatment of schizophrenia are well established: the development of cognitive- enhancing drugs, the development of drugs to treat negative symptoms, improved treatment options for treatment-resistant patients, the development of drugs with enhanced safety profiles and the development of drugs to increase compliance.

Thus, current treatments for schizophrenia rely on a high number of established atypical antipsychotic products that are able to effectively manage the positive symptoms of the disorder and the most pressing unmet needs are for novel and effective therapies to treat the negative symptoms and cognitive impairments also associated with schizophrenia. There is currently only one drug, clozapine, available for treatment-resistant patients (patients who fail to respond to at least two or more different antipsychotics), which is associated with severe side effects. A portion of patients remain resistant to clozapine treatment, and as such, another significant unmet need is for the improvement of treatment options for treatment-resistant patients. While there are a large number of approved drugs for the treatment of schizophrenia, they do not significantly differ from each other in terms of efficacy, but may have a slightly different safety profile in a particular patient. Due to the high number of side effects seen with all treatments, there is a large unmet need for efficacious drugs with an improved safety profile

The role of 5-HT6R antagonists in several neurological disorders has been described over the past two decades and reported as a novel target for cognitive enhancement in Alzheimer’s Disease or Schizophrenia (de Bruin & Kruse, 2015. Curr Pharm Des. 2l(26):3739-59). However, clinical trials involving the use of 5-HT6R antagonists for the treatment of schizophrenia have resulted in failure. For example, use of idalopirdine to treat cognitive impairment in Schizophrenia patients failed at Phase II (EduraCT number: 2008-001441-26).

There is a large amount of literature concerning the potential use of 5-HT3R antagonists for the treatment of cognitive impairment (Meneses, 1998. Rev Neurosci. 9(4):275-89). Further, three selective 5-HT3R antagonists are undergoing clinical trials for Schizophrenia. However, all of these clinical trials use 5-HT3R as a form of adjunctive therapy in combination with, for example, haloperidol or risperidone (Andrade, 2014. J Clin Psychiatry. 75(7):e707-9; Garay el al., 2016. Expert Opin Investig Drugs. 25(2): 159-70).

Thus, there is currently no evidence that 5-HT3R antagonists or 5-HT6R antagonists have any effect on the positive symptoms of Schizophrenia. In fact, 5-HT6R antagonists have been shown to have no effect on the positive symptoms of Schizophrenia.

The effect of SB-271046, a specific 5-HT6 receptor antagonist, in three models for the positive symptoms of schizophrenia— D-amphetamine-induced hyperactivity, and D-amphetamine- or phencyclidine (PCP)-disrupted prepulse inhibition (PPI) was studied and from the results it is clear that SB-271046 is not expected to have an antipsychotic efficacy, at least when given as monotherapy (Pouzet et al., 2002. Pharmacol Biochem Behav. 7l(4):635-43). Further, two selective 5-HT6 receptor antagonists, Ro04-6790 and Ro65-7l99, failed in three drug-induced models of PPI disruption and on latent inhibition (LI) utilizing a conditioned lick suppression (CLS) procedure, as antipsychotic models (Leng et al., 2003. Pharmacol Biochem Behav. 75(2):28l-8).

Even though the detrimental effects of Schizophrenia on the individual and society at large are known and well documented, it is commonly agreed in the medical community that one of the main unmet needs in the treatment of Schizophrenia is a composition which can treat cognition impairment while also preventing or treating Schizophrenia-triggered psychosis. It is therefore an objective of the present application to provide a composition which can treat and/or prevent some of the positive symptoms of Schizophrenia, i.e. psychosis, while also treating and/or preventing the cognitive impairment associated with Schizophrenia.

Figures

Figure 1: Effect of Compound 6 of Table 1 on low frequency oscillations of the medial prefrontal cortex after the rat had been administered PCP. A) Spectrogram showing the frequency over time. B) Histogram representation of the data shown in (A).

Figure 2: Effect of Ondansetron on low frequency oscillations of the medial prefrontal cortex after the rat had been administered PCP. A) Spectrogram showing the frequency over time. B) Histogram representation of the data shown in (A).

Figure 3: Effect of SB-399885 on low frequency oscillations of the medial prefrontal cortex after the rat had been administered PCP. A) Spectrogram showing the frequency over time. B) Histogram representation of the data shown in (A).

Figure 4: Effect of SB-399885 and Ondansetron on low frequency oscillations of the medial prefrontal cortex after the rat had been administered PCP. A) Spectrogram showing the frequency over time. B) Histogram representation of the data shown in (A).

Figure 5: Preventative effects of Compound 6 on the changes in gamma oscillations and fast oscillations in the prefrontal cortex as well as the changes in the fast oscillation on the nucleus accumbens induced by PCP. A) Spectrogram showing the frequency over time and the time at which the rats were administered vehicle and PCP. B) Spectrogram showing the frequency over time and the time at which the rats were administered Compound 6 and PCP. C) Gamma oscillations in the prefrontal cortex over time. Arrows indicate when Compound 6 or vehicle and PCP were administered. D) Fast oscillations in the prefrontal cortex over time. Arrows indicate when Compound 6 or vehicle and PCP were administered. E) Fast oscillations in the nucleus accumbens over time. Arrows indicate when Compound 6 or vehicle and PCP were administered.

Summary of the invention

There is extensive literature on the role of 5-HT6 receptors or 5-HT3 receptors in circuits related to cognition improvement, including clinical trials with positive results up to phase II. There is also extensive literature about the mechanistic aspects of the cognition pathways. However, after sound failures of the more advanced 5-HT6R antagonist compounds in phase III and not enough robust clinical data supporting a 5-HT3R antagonist, the use of 5-HT3R or 5-HT6R as targets is not considered to be robust enough to support the use of an antagonist directed to either receptor as an effective monotherapy. Some reports suggest their use as an adjuvant therapy in combination with already known antipsychotic treatments. So, the established idea in the literature is that 5-HT6R or 5- HT3R antagonists could be useful as adjunctive therapies with established antipsychotic treatments in order to compensate for the negative side effects that antipsychotic treatments might have on the cognition of the subject.

The“in vitro” full characterization by the inventors of one of the compounds disclosed in WO 2015/012704 Al, discovered that among the originally described 5-HT6R antagonist family there was an equipotent subfamily against 5-HT3R and approximately 2 orders of magnitude less potent against a battery of 93 primary molecular targets including 13 enzymes, 80 binding assays and CYP profile (Table 2).

This was a surprising find because WO 2015/012704 Al only discloses that the compounds are 5- HT6R antagonists and, to the knowledge of the inventors, compounds with both 5-HT3R and 5-HT6R antagonist activity at the low nanomolar level and with no other low nanomolar activity to related receptors (Table 2) have not been described before in the literature. On the basis of previous clinical knowledge on the effect of a 5-HT6R or 5-HT3R antagonists as monotherapies, the inventors hypothesized that a dual antagonist on 5-HT6R and 5-HT3R could be used to provide a robust adjuvant therapy to treat cognitive impairment.

To test the theory that the dual antagonist would be more potent than the administration of a 5-HT6R antagonist or 5-HT3R antagonist, the inventors used several in vivo models. The inventors tested classic memory and learning models, but were not able to discriminate between the effects of the dual antagonists or the mono-antagonists. By moving to electrophysiological models, the inventors hoped to observe a difference in the effect of the dual antagonist versus the mono-antagonists.

The surprise came when the inventors explored the PCP-induced reduction of low frequency oscillations in the prefrontal cortex of anesthetized rats ln this model PCP, an NMDA antagonist that is frequently used to generate schizophrenia models in mice and rats, reduces the power of low frequency oscillations in the mPFC. The model is of interest because classical antipsychotics (haloperidol, chlorpromazine, perphenazine) and atypical (clozapine, olanzapine, quetiapine, risperidone, ziprasidone, aripripazole, brexpiprazole) are able to revert the effect of PCP on the low frequency oscillations (Llado-Perfort et al, 2016. Eur Neuropsychopharmacol; 26(3):6l4-25), whereas for example an antidepressant compound won’t do anything. Consistent with all prior reports, neither an archetypical 5-HT3R antagonist (ondansetron) nor an archetypical 5-HT6R antagonist (SB399885) were able to revert the PCP effect, confirming that these compounds by themselves are not able to restore the physiological excitatory/inhibitory balance altered by PCP and so are not well suited for the treatment of Schizophrenia without an additional antipsychotic. It is worth noting that ondansetron or SB399885 were as active as a dual antagonist in parallel experiments in memory and cognition paradigms at the doses used by the inventors. However, the inventors were extremely surprised to find that the administration of the dual antagonist was enough to revert the PCP effect. Further, the dual antagonist appeared to be as effective as the best-known antipsychotics. This surprising finding was then further confirmed when ondansetron and SB399885 were co-administered and the same effect was achieved.

Thus, in a first aspect, the present invention provides a composition comprising one or more agent(s) for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the one or more agent(s) has or have 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity.

In a second aspect, the present invention provides an agent with 5-HT6 receptor antagonist activity for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the agent is co administered with a second agent and the second agent has 5-HT3 receptor antagonist activity.

In a third aspect, the present invention provides an agent with 5-HT3 receptor antagonist activity for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the agent is co administered with a second agent and the second agent has 5-HT6 receptor antagonist activity.

In a fourth aspect, the present invention provides a kit comprising one or more agent(s) that has or have 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity, and a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent and/or a pharmaceutically acceptable excipient for use in the manufacture of an anti-psychotic.

Detailed description of the invention

Definitions

General terms used in the description of compounds bear their usual meanings. The term“alkyl” as used herein denotes a univalent saturated branched or straight hydrocarbon chain. Unless otherwise stated such chains can contain from 1 to 3 carbon atoms. Representative of such alkyl groups are methyl, ethyl, propyl, isopropyl and the like. The same carbon content applies to the patent term “alkane”, and to derivative terms such as“alkoxy”. The carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety.“Alkyl(C_rCy” for example, means methyl, ethyl, n-propyl or isopropyl. The term“ aryl” encompasses monocyclic or fused bicyclic aromatic or hetero-aromatic groups, including but not limited to furyl, thienyl, pyrroryl, oxazolyl, thiazolyl, imidazolyl, imidazo[2,l- b][l,3]thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pirymidinyl, pyrazinyl, 1,3,5- triazinyl, phenyl, 1 //-indazol-7-yl, 1 //-indazol-6-yl, 1 //-indol-2-yl, 1 //-indol-3-yl, 1 //-indol-6-yl, 1 H- indol-7-yl, indolizinyl, isoindolyl, 1 -benzofuran-2-yl, l-benzofuran-3-yl, l,2,3,4-tetrahydronaphtyl,

1.2.3.4-tetrahydroisoquinolinyl, indanyl, indenyl, l-benzothien-3-yl, 1 -benzothien-2-yl, 2,3-dihydro-

1.4-benzodioxin-5-yl, benzimidazolyl, l,3-benzothiazol-4-yl, l,3-benzothiazol-5-yl, benzot[l,2,5]thiaz-diazolyl, quinolinyl, isoquinolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, 1,8- naphthyridinyl, naphtyl, pteridinyl or azulenyl.“Halo" or“ Halogen” means chloro, fluoro, bromo or iodo;“ hetero” as in“ heteroalkyl”,“ heteroaromatic” etc. means containing one or more N, O or S atoms,“ heteroalkyl” includes alkyl groups with heteroatoms in any position, thus including N-bound O-bound or S-bound alkyl groups.

The term“ substituted ^r” means that the specified group or moiety bears one or more substituents. Where any group may carry multiple substituents, and a variety of possible substituents is provided, the substituents are independently selected, and need not be the same. The term“unsubstituted’^, means that the specified group bears no substituents.

N-oxides of the compounds mentioned in the present document belong to the invention. Tertiary amines may or may not give rise to N-oxide metabolites. The extent to what N-oxidation takes place varies from trace amounts to a near quantitative conversion. N-oxides may be more active than their corresponding tertiary amines, or less active. While N-oxides can easily be reduced to their corresponding tertiary amines by chemical means, in human body this happens to varying degrees. Some N-oxides undergo nearly quantitative reductive conversion to the corresponding tertiary amines, in other cases it is a mere trace reaction, or even completely absent.

The terms " selective " and " selectivity " refer to compounds that display affinity towards a particular receptor (e.g. a 5-HT6 receptor) without displaying substantial cross-affinity towards another receptor (e.g. other 5-HT receptor sub-types). Thus, for example, selective compounds of the present invention may display affinity towards 5-HT6 receptors and/or 5-HT3 receptors without displaying substantial cross-affinity towards other 5-HT receptors (including 5-HT1, 5-HT2, 5-HT4, 5-HT5 and/or 5-HT7) or D receptors (including Dl, D2, D3 or D4 receptor) ln one embodiment, an agent of the present invention has at least about 10 fold selectivity to the 5-HT6 receptor and/or 5-HT3 receptor, at least about 50 fold selectivity to the 5-HT6 receptor and/or 5-HT3 receptor, at least about 100 fold selectivity to 5-HT6 receptor and/or 5-HT3 receptor, at least about 250 fold selectivity to 5-HT6 receptor and/or 5-HT3 receptor, or at least about 500 fold selectivity to the desired target(s). The term“IC50” refers to the half maximal inhibitory concentration (IC50) which is a measure of the potency of a substance in inhibiting a specific biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half.

The terms“ individual”,“patient” or“subject” are used interchangeably in the present application to designate a human being and are not meant to be limiting in any way. The“individual” ,“patient” or “subject” can be of any age, sex and physical condition. The term“animal”, as used in the present application, refers to any multicellular eukaryotic heterotroph which is not a human. In a preferred embodiment, the animal is selected from a group consisting of cats, dogs, pigs, ferrets, rabbits, gerbils, hamsters, guinea pigs, horses, rats, mice, cows, sheep, goats, alpacas, camels, donkeys, llamas, yaks, giraffes, elephants, meerkats, lemurs, lions, tigers, kangaroos, koalas, bats, monkeys, chimpanzees, gorillas, bears, dugongs, manatees, seals and rhinoceroses.

As used herein, " 'pharmaceutically acceptable carrier " or“ pharmaceutically acceptable diluent” means any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and, without limiting the scope of the present invention, include: additional buffering agents; preservatives; co-solvents; antioxidants, including ascorbic acid and methionine; chelating agents such as EDTA; metal complexes (e.g., Zn-protein complexes); biodegradable polymers, such as polyesters; salt forming counterions, such as sodium, polyhydric sugar alcohols; amino acids, such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamic acid, and threonine; organic sugars or sugar alcohols, such as lactitol, stachyose, mannose, sorbose, xylose, ribose, ribitol, myoinisitose, myoinisitol, galactose, galactitol, glycerol, cyclitols (e.g., inositol), polyethylene glycol; sulfur containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, [alpha] -monothioglycerol, and sodium thio sulfate; low molecular weight proteins, such as human serum albumin, bovine serum albumin, gelatin, or other immunoglobulins; and hydrophilic polymers, such as polyvinylpyrrolidone. Other pharmaceutically acceptable carriers, excipients, or stabilizers, such as those described in Remington: The Science and Practice of Pharmacy 22^nd edition, Pharmaceutical press (2012), ISBN-13: 9780857110626 may also be included.

The term“receptor” refers to a protein molecule present on the membrane or in the interior of the cell that receives chemical signals (i.e., interacts with endogenous and/or exogenous molecules), leading to: a) the blockade of the said protein molecule (e.g. as caused by receptor antagonists); or b) a cellular response upon binding to the chemical signals (e.g. as caused by receptor agonists, partial agonists, inverse agonists and allosteric modulators). The term“ receptor antagonist” as used in the present application refers to a type of receptor ligand and/or drug that blocks or dampens agonist- or partial agonist-mediated responses rather than provoking a biological response itself upon binding to a receptor. As used in the present application, the term“ receptor antagonist” may also refer to a type of receptor ligand and/or drug that activates the receptor to produce a biological response that is opposed to that produced by a full or partial agonist. Although these compounds are technically known as “ inverse agonists”, here we use the term“ receptor antagonist” to encompass both antagonists and inverse agonists. Both antagonists and inverse agonists effectively counteract the effects of agonists (full or partial).

The term“ 5-HT3R” or“5-HT3 receptor” refers to a receptor belonging to the Cys-loop superfamily of ligand-gated ion channels. The 5-HT3 receptor is made up of five subunits (encoded by the genes HTR3A, ATR3B, HTA3a, HTR3D, and/or HTR3E) arranged around a central ion conducting pore. A functional channel may be composed of either five identical 5-HT3A subunits (homopentameric) or a mixture of 5-HT3A and one of the other four receptor subunits (5-HT3B, 5-HT3C, 5-HT3D, 5-HT3E) (heteropentameric) The 5-HT3R is found in humans and the different subunits of the receptor has been sequenced, characterized and the data have been deposited in the UniProtKB database under the accession number P46098, 095264, A5X5Y0, Q70Z44 and/or Q8WXA8. The term“ 5-HT3R” may also refer to a homologue in another species which has the same function as the 5-HT3R in humans or to any biological combination of receptor subunits to form the pentameric complex.

The term“ 5-HT6R” or“5-HT6 receptor” refers to a G protein-couple receptor which mediates excitatory neurotransmission. The 5-HT6R is found in humans and the receptor has been sequenced, characterized and the data have been deposited in the UniProtKB database under the accession number P50406. The term“ 5-HT6R” may also refer to a homologue in another species which has the same function as the 5-HT6R in humans.

The term“D2 receptor” or“ D2R” refers to a subtype of the dopamine receptor. The D2R is found in humans and the receptor has been sequenced, characterized and the data have been deposited in the UniProtKB database under the accession number P 14416. The term“ D2R” may also refer to a homologue in another species which has the same function as the D2R in humans.

The terms“treatment" and“ therapy”, as used in the present application, refer to a set of hygienic, pharmacological, surgical and/or physical means used with the intent to cure and/or alleviate a disease and/or symptoms with the goal of remediating the health problem. The terms“ treatment” and “ therapy” include preventive and curative methods, since both are directed to the maintenance and/or reestablishment of the health of an individual or animal. Regardless of the origin of the symptoms, disease and disability, the administration of a suitable medicament to alleviate and/or cure a health problem should be interpreted as a form of treatment or therapy within the context of this application.

The term“ prevention”, as used in the present application, refers to a set of hygienic, pharmacological, surgical and/or physical means used to prevent the onset and/or development of a disease and/or symptoms. The term“ prevention” encompasses prophylactic methods, since these are used to maintain the health of an animal or individual.

Any of the agents or compositions of the present invention are used to treat and/or prevent schizophrenia and/or psychosis. In a preferred embodiment, the agents or compositions of the present invention are used to treat and/or prevent psychosis in an individual or animal who suffers from schizophrenia.

The term“agent” refers to any substance which functions as a 5-HT3R antagonist and/or 5-HT6R antagonist. An agent may be a protein, nucleic acid molecule, compound, etc. which binds to the 5- HT3R and/or 5-HT6R. In a preferred embodiment, the one or more agent(s) is/are a compound(s) which functions as a 5-HT3R antagonist and/or 5-HT6R antagonist. In a preferred embodiment, the one or more agent(s) is/are a selective 5-HT3R antagonist and/or 5-HT6R antagonist.

The term“ psychosis” refers to any abnormal condition of the mind that results in difficulties telling what is real and what is not. In the case of Schizophrenia, psychosis can be a positive symptom of the disease. In a preferred embodiment, the compositions of the present invention are used to treat and/or prevent psychosis in a subject or animal who suffers from Schizophrenia.

Compositions and agents for use

In a first aspect, the present invention provides a composition comprising one or more agent(s) for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the one or more agent(s) has or have 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity. In a preferred embodiment, the one or more agent(s) has an IC50 for the D2 receptor that is at least 10 times higher than the IC50 for the 5-HT6 receptor and the 5-HT3 receptor.

In an alternative aspect, the present invention provides a composition comprising a first agent that has 5-HT6 receptor antagonist activity and a second agent that has 5-HT3 receptor antagonist activity for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein

i. the first agent has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT6 receptor, ii. the second agent has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT3 receptor, and

iii. the first and second agent may be the same or different agents.

In a preferred embodiment, the composition comprises an agent with 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity. In an alternative embodiment, the composition comprises a first agent with 5-HT6 receptor antagonist activity and a second agent with 5-HT3 receptor antagonist activity, wherein, optionally:

i. the agent with 5-HT6 receptor antagonist activity is a selective 5-HT6 receptor antagonist that has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT6 receptor, and

ii. the agent with 5-HT3 receptor antagonist activity is a selective 5-HT3 receptor antagonist that has an IC50 for the D2 receptor at least 10 higher than times the IC50 for the 5-HT3 receptor.

In a second aspect, the present invention provides an agent with 5-HT6 receptor antagonist activity for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the agent is co administered with a second agent and the second agent has 5-HT3 receptor antagonist activity, wherein, optionally

i. the agent with 5-HT6 receptor antagonist activity is a selective 5-HT6 receptor antagonist that has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT6 receptor, and

In a third aspect, the present invention provides an agent with 5-HT3 receptor antagonist activity for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the agent is co administered with a second agent and the second agent has 5-HT6 receptor antagonist activity, wherein, optionally

i. the agent with 5-HT3 receptor antagonist activity is a selective 5-HT3 receptor antagonist that has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT3 receptor.

Methods to determine whether an agent binds to 5-HT6R and/or 5-HT3R are known in the art. For example, protocols are available at the PDSP (Psychoactive Drug Screening Program) - NIMH (National Institute of Mental Health) website (https://pdspdb.unc.edu/pdspWeb/). The website provides an assay protocol book (Roth, 2013. National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP) ASSAY PROTOCOL BOOK Version II. https://pdspdb.unc.edu/pdspWeb/content/PDSP%20Protocols%20II%2020l3-03-28.pdf). Thus, it would not be an undue burden to identify agents that have 5-HT6R and/or 5-HT3R antagonist activity. In any case, the 5-HT3 and D2 affinity could be measured, as IC50, according to the methods described in the present application and the 5-HT6 could be measured using the methods described in WO 2015/012704 Al.

In a preferred embodiment, any of the agents or compositions disclosed herein is used for the treatment and/or prevention of psychosis in an individual or animal who/that suffers from schizophrenia.

Agents with 5-HT6R and 5-HT3R antagonist activity

In some embodiments, the agent has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT6 receptor and 5-HT3 receptor. Preferably, the agent has an IC50 for the D2 receptor at least 20 times higher than the IC50 for the 5-HT6 receptor and 5-HT3 receptor. More preferably, the agent has an IC50 for the D2 receptor at least 50 times higher than the IC50 for the 5-HT6 receptor and 5-HT3 receptor. Most preferably, the agent has an IC50 for the D2 receptor at least 100 times higher than the IC50 for the 5-HT6 receptor and 5-HT3 receptor.

In a preferred embodiment, the agent is a compound according to Formula (I):

wherein:

R¹, R² independently represent hydrogen, an unsubstituted alkyl(Ci-C3) group, an alkyl(Ci-C3) group substituted with one or more halogen atoms or an alkoxyl(Ci-C3) group, or independently a group selected from: cyano, nitro, amino or hydroxyl;

R⁴ represents CO, CH₂, substituted alkyl(Ci-C₂) group, SO or S0₂;

R⁵ represents an (i) unsubstituted or substituted aryl (5-6 membered), (ii) unsubstituted or substituted biaryl (8-10 membered), (iii) unsubstituted or substituted heteroaryl (5-6 membered) having 1-3 heteroatoms independently selected from the group consisting of N, O and S, or (iv) unsubstituted or substituted hetero-biaryl (8-10 membered) having 1-3 heteroatoms independently selected from the group consisting of N, O and S, wherein, optionally the substituted aryl, biaryl, heteroaryl or hetero biaryl is substituted with one or more substituents selected from an alkyl(Ci-C4) group, alkyl(Ci-C3) group substituted with one or more halogen atoms, alkoxy(Ci-C₃) group, alkenyl(C₂-C₄), halogen, nitro, hydroxyl, cyano, amino, alkylamino or carboxamide; and

R³ represents a substituent consisting of Formula (II):

wherein:

A represents NH, O, CH₂ or NR⁶;

R⁶ is an alkyl(Ci-C₃) group, benzyl or a carboxyl(Ci-C₃) group substituted with an alkyl(Ci-C₄) group; m is selected from 0, 1 or 2; and

n is selected from 0, 1 or 2; or

a tautomer, stereoisomer, /V-oxidc, isotopically-labeled analogue, pharmaceutically acceptable salt, hydrate or solvate thereof.

Methods for synthesizing the above compounds are disclosed in WO 2015/012704 Al. ln a preferred embodiment, R⁴ represents CO, CH₂, substituted alkyl(Ci-C₂) group, SO or S0₂, wherein the alkyl(Ci-C₂) group is substituted with one or more substituents selected from an alkyl(Cr C₃) group, alkyl(Ci-C₃) group substituted with one or more halogen atoms, alkoxy(Ci-C₃) group, alkenyl(C₂-C₄), halogen, nitro, hydroxyl, cyano, amino, alkylamino or carboxamide ln an alternative embodiment, R⁴ represents CO, CH₂, alkyl(Ci-C₂) group, SO or S0₂. ln a preferred embodiment, the agent is selected from any one of the compounds disclosed in Table 1.

Table 1

Binding data for, inter alia, 5-HT_IA, 5-HT_2c, 5-HT₆, 5-HT₇ and D₂ for some of the above compounds is disclosed in Tables 1-4 of WO 2015/012704 Al . In a preferred embodiment, the agent is selected from the group consisting of compounds 6, 18, 34 and 36 of Table 1. More preferably, the agent is selected from the group consisting of compounds 6, 18 and 36 of Table 1.

The 1UPAC names may be converted into chemical structures using any means known to the skilled person. Such means include“OPSIN: Open Parser for Systematic IUPAC nomenclature v. 2.3.7” which is able to automatically convert the 1UPAC names into chemical structures (Lowe el al., 201 1. J. Chem. Inf. Model. 5l(3):739-53).

Agents with 5-HT6R antagonist activity

5-HT6R antagonists are well known in the art (for a review of some of the available 5-HT6 receptor antagonists see Liu & Robichaud, 2010. Int Rev Neruobiol. 94: 1-34). Thus, a skilled person would have no issue in identifying suitable compounds which could be used in the present invention. The first selective 5-HT6 receptors ligands were identified by a high throughput screening of library of compounds, which resulted in the selection of the antagonist SB-271046. It was the first 5-HT6 receptor agent that entered clinical trials for cognitive impairment in schizophrenia and Alzheimer's disease.

At the same time, a series of tryptamine derivatives based around EMDT was reported as 5- HT6R agonists. In a next move, arylsulfonamide derivatives of indole and indole-like structures were designed. It was found, that compound MS-245 displayed high affinity for 5-HT6 receptors and high selectivity over other monoaminergic receptors. Moreover, an introduction of the sulfonamide moiety switched the functional profile from agonistic to antagonistic one.

Since that time, several 5-HT6 ligands possessing sulfonyl or sulfonamide moiety have been developed. Chemically, they might be divided into two main groups. The first one consists in the indole and indole-like based structures. Among them PF-05212365 is currently under clinical development for the treatment of cognitive deficits in schizophrenia and Alzheimer’s disease.

The second group comprises arylpiperazine derivatives, containing one or more condensed aromatic rings. PRX-07034 belongs to monoarylpiperazine derivatives modified with sulfonyl moiety. Other arylpiperazine derivatives with planar aromatic systems, e.g. SB-742457 and R-1485 are the subject of clinical trials for cognitive impairment in schizophrenia and Alzheimer's disease.

It is worth noting that the above mentioned structures, adapt in the pharmacophore models for 5-HT6 receptors antagonists, independently developed by Pullaguria (Pullaguria el al., 2004. Bioorg Med Chem Lett. 14(17):4569-73) and Lopez-Rodriguez (Lopez-Rodriguez el al, 2005. ./. Med. Chem. 48(7):2548-2558). The key elements proposed in these models are the two hydrophobic regions, double hydrogen bond acceptor (mainly sulfonyl or sulfonamide moiety) and the basic center of the molecule.

Although the sulfonyl or sulfonamide group may be replaced by its amide or alkyl bioisoster or carboxamide group (US 2003/0232843 Al; WO 2005/030724 Al), arylsulfonyl and arylsulfonamide derivatives remain an important class of 5-HT6 ligands. Several patent publications e.g. US 8,003,670, US 6,423,717, US 7,960,374 B2, US 2009/0069337 Al, WO 2011/044134 Al, EP 2 069 310 Bl, disclose several classes of arylsulfonamides, and claim their potential application in the treatment of CNS disorders related to disturbance of 5-HT6 receptor functions.

In some embodiments, the agent with 5-HT6 receptor antagonist activity has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT6 receptor. Preferably, the agent has an IC50 for the D2 receptor at least 20 times higher than the IC50 for the 5-HT6 receptor. More preferably, the agent has an IC50 for the D2 receptor at least 50 times higher than the IC50 for the 5- HT6 receptor. Most preferably, the agent has an IC50 for the D2 receptor at least 100 times higher than the IC50 for the 5-HT6 receptor.

In a preferred embodiment, the agent with 5-HT6R antagonist activity is a compound according to Formula (I):

wherein:

R¹, R² independently represent hydrogen, an unsubstituted alkyl(Ci-C3) group, an alkyl(Ci-C3) group substituted with one or more halogen atoms or an alkoxyl(Ci-C3) group, or independently a group selected from: cyano, nitro, amino or hydroxyl;

R⁴ represents CO, CH₂, substituted alkyl(Ci-C2) group, SO or S0₂;

R⁵ represents an (i) unsubstituted or substituted aryl (5-6 membered), (ii) unsubstituted or substituted biaryl (8-10 membered), (iii) unsubstituted or substituted heteroaryl (5-6 membered) having 1-3 heteroatoms independently selected from the group consisting of N, O and S, or (iv) unsubstituted or substituted hetero-biaryl (8-10 membered) having 1-3 heteroatoms independently selected from the group consisting of N, O and S, wherein, optionally the substituted aryl, biaryl, heteroaryl or hetero biaryl is substituted with one or more substituents selected from an alkyl(Ci-C4) group, alkyl(Ci-C3) group substituted with one or more halogen atoms, alkoxy(Ci-C3) group, alkenyl(C₂-C4), halogen, nitro, hydroxyl, cyano, amino, alkylamino or carboxamide; and

R³ represents a substituent consisting of Formula (11), Formula (111), Formula (IV) or Formula (V):

wherein:

A represents NH, O, CH₂ or NR⁶;

B represents NH, O or NR⁷;

R⁶ is an alkyl(Ci-C3) group, benzyl or a carboxyl(Ci-C3) group substituted with an alkyl(Ci-C4) group; R⁷ is a hydrogen atom or alkyl(Ci-C3) group;

R⁸ is an alkyl(Ci-C3) group; m is selected from 0, 1 or 2;

n is selected from 0, 1 or 2; and

1 is selected from 1 or 2; or

a tautomer, stereoisomer, V-oxide, isotopically-labeled analogue, pharmaceutically acceptable salt, hydrate or solvate thereof.

Methods for synthesizing the above compounds are disclosed in WO 2015/012704 Al.

In a preferred embodiment, the agent with 5-HT6R antagonist activity is selected from a list consisting of SB-271046 (CAS No: 209481-24-3), SB-357134 (CAS No: 219963-52-7), SB-399885 (CAS No: 402713-80-8), Ro04-6790 (CAS No: 202466-68-0), Ro65-7l99 (CAS No: 350800-83-8), AVN-211 (CAS No: 1173103-84-8), idalopirdine (CAS No: 467459-31-0), MS-245 (CAS No: 275363-58-1), PF-05212365 (CAS No: 925448-93-7), PRX-07034 (CAS No: 903580-39-2), SB-742457 (CAS No: 607742-69-8), R-1485 (PubChem ID: 90488993) PF-5212377 (Compound ID: CHEMBL3545344), Cerlapirdine (CAS No: 925448-93-7), SUVN-502 (CAS No: 701205-60-9), SYN-120 (CAS No: 1000308-25-7), AVN-101 (CAS No: 1025725-91-0), AVN-397 (Avineuro Pharmaceuticals), AVN- 457 (Avineuro Pharmaceuticals), AVN-458 (Avineuro Pharmaceuticals), AVN-492 (Avineuro Pharmaceuticals), AVN-322 (Ivachtchenko et al., 2017. Curr Alzheimer Res. l4(3):268-294), ABT- 354 (Abbott Laboratories), BVT-5182 (l-benzenesulfonyl-4-(piperazin-l-yl)-indole), BVT-74316 (N- (2-methoxy-5-methylphenyl)-7-(piperidin-4-yloxy)-l-benzofuran-5-sulfonamide), JNJ-39269646 (4- phenyl-6-piperazin-l-yl-3-(trifluoromethyl)pyridazine), MEM-68626 (Rowe et al, 2008. “Characterization of serotonin 5-HT6 receptor antagonists as putative drugs for age-related mild cognitive impairment and Alzheimer’s disease.” SfN Neuroscience Meeting Planner, 685.9), Ro- 4368554 (CAS No: 478082-99-4), ADN-5127, ADN-0965, ADN-1184 (Partyka et al, 2016. Naunyn Schmiedebergs Arch Pharmacol. 389: 593-602), ADN-2013 and ADN-3662. Preferably, the agent with 5-HT6R antagonist activity is selected from a list consisting of SB-271046, SB-357134, SB- 399885, Ro04-6790, Ro65-7l99, AVN-211, idalopirdine, MS-245, PF-05212365, PRX-07034, SB- 742457, R-1485, Cerlapirdine, SUVN-502, SYN-120, AVN-101, AVN-322, BVT-5182, BVT-74316, JNJ-39269646 and Ro-4368554. More preferably, the agent with 5-HT6R antagonist activity is SB- 399885.

Agents with 5-HT3R antagonist activity

5-HT3R antagonists are well known in the art (for a review of some of the available 5-HT3 receptor antagonists see Smith et al, 2012. Ann Palliat Med. 1 (2): 115-20). Thus, a skilled person would have no issue in identifying suitable compounds which could be used in the present invention. In some embodiments, the agent with 5-HT3 receptor antagonist activity has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT3 receptor. Preferably, the agent has an IC50 for the D2 receptor at least 20 times higher than the IC50 for the 5-HT3 receptor. More preferably, the agent has an IC50 for the D2 receptor at least 50 times higher than the IC50 for the 5- HT3 receptor. Most preferably, the agent has an IC50 for the D2 receptor at least 100 times higher than the IC50 for the 5-HT3 receptor.

In a preferred embodiment, the agent with 5-HT3R antagonist activity is a compound according to Formula (VI):

wherein:

R¹ represents a C_3.7 cycloalkyl, C_1.4 alkyl group or a C_3.10 alkynyl group; and

R², R³ and R⁴ is a hydrogen atom or a Ci_6 alkyl, C3.7 cycloalkyl, C2-6 alkenyl or phenyl-(Ci_3)alkyl group and each of the other two groups, which may be the same or different represents a hydrogen atom or a Ci_6 alkyl group; or

a tautomer, stereoisomer, V-oxide, isotopically-labeled analogue, pharmaceutically acceptable salt, hydrate or solvate thereof. Compounds of Formula (VI) were described in US 4,695,578.

In a preferred embodiment, the agent with 5-HT3R antagonist activity is selected from a list consisting of vabicaserin (CAS No: 620948-93-8 or 887258-95-9), ondansetron (CAS No: 99614-01-4, 99614- 02-5 or 103639-04-9), tropisetron (CAS No: 105826-92-4), granisetron (CAS No: 107007-99-8), dolasetron (CAS No: 115956-12-2), palonosetron (CAS No: 135729-62-3), ramosetron (CAS No: 132907-72-3), cilansetron (CAS No: 120635-74-7), vortioxetine (CAS No: 508233-74-7), alsoetron (CAS No: 122852-42-0), DAU 6215 (CAS No: 123258-84-4), GF038032F, WAY 100289 (CAS No: 136013-69-9), TAK-058 (WO 2014/014951 Al), R3487/MEM3454 (Rezvani et al, 2009. Prog Neuropsychopharmacol Biol Psychiatry. 33(2):269-75) and EVP-5141 (Boess et al., 2013. Psychopharmacology ( Bert ^'). 227(1): 1-17). Preferably, the agent with 5-HT3R antagonist activity is selected from a list consisting of vabicaserin, ondansetron, tropisetron, granisetron, dolasetron, palonosetron, ramosetron, cilansetron, vortioxetine, alsoetron, DAU 6215, WAY 100289, TAK-058, R3487/MEM3454 and EVP-5141. More preferably, the agent with 5-HT3R antagonist activity is ondansetron.

Pharmaceutical composition

In a preferred embodiment, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent and/or a pharmaceutically acceptable excipient.

A pharmaceutical composition as described herein may also contain other substances. These substances include, but are not limited to, cryoprotectants, lyoprotectants, surfactants, bulking agents, anti-oxidants, and stabilizing agents. In some embodiments, the pharmaceutical composition may be lyophilized.

The term " cryoprotectanf as used herein, includes agents which provide stability to the agents against freezing-induced stresses. Cryoprotectants may also offer protection during primary and secondary drying and long-term product storage. Non-limiting examples of cryoprotectants include sugars, such as sucrose, glucose, trehalose, mannitol, mannose, and lactose; polymers, such as dextran, hydroxyethyl starch and polyethylene glycol; surfactants, such as polysorbates (e.g., PS-20 or PS-80); and amino acids, such as glycine, arginine, leucine, and serine. A cryoprotectant exhibiting low toxicity in biological systems is generally used.

In one embodiment, a lyoprotectant is added to a pharmaceutical composition described herein. The term " lyoprotectant " as used herein, includes agents that provide stability to the agents during the freeze-drying or dehydration process (primary and secondary freeze- drying cycles. This helps to minimize product degradation during the lyophilization cycle, and improve the long-term product stability. Non-limiting examples of lyoprotectants include sugars, such as sucrose or trehalose; an amino acid, such as monosodium glutamate, non-crystalline glycine or histidine; a methylamine, such as betaine; a lyotropic salt, such as magnesium sulfate; a polyol, such as trihydric or higher sugar alcohols, e.g., glycerin, erythritol, glycerol, arabitol, xylitol, sorbitol, and mannitol; propylene glycol; polyethylene glycol; pluronics; and combinations thereof. The amount of lyoprotectant added to a pharmaceutical composition is generally an amount that does not lead to an unacceptable amount of degradation when the pharmaceutical composition is lyophilized.

In some embodiments, a bulking agent is included in the pharmaceutical composition. The term " bulking agent " as used herein, includes agents that provide the structure of the freeze- dried product without interacting directly with the pharmaceutical product. In addition to providing a pharmaceutically elegant cake, bulking agents may also impart useful qualities in regard to modifying the collapse temperature, providing freeze-thaw protection, and enhancing the stability over long-term storage. Non-limiting examples of bulking agents include mannitol, glycine, lactose, and sucrose. Bulking agents may be crystalline (such as glycine, mannitol, or sodium chloride) or amorphous (such as dextran, hydroxyethyl starch) and are generally used in formulations in an amount from 0.5% to 10%.

Other pharmaceutically acceptable carriers, excipients, or stabilizers, such as those described in Remington's Pharmaceutical Sciences l6th edition, Osol, A. Ed. (1980) or Remington: The Science and Practice of Pharmacy 22^nd edition, Pharmaceutical press (2012), ISBN-13: 9780857110626 may also be included in a pharmaceutical composition described herein, provided that they do not adversely affect the desired characteristics of the pharmaceutical composition.

For solid pharmaceutical compositions, conventional nontoxic solid carriers may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. For solution for injection, the pharmaceutical composition may further comprise cryoprotectants, lyoprotectants, surfactants, bulking agents, anti-oxidants, stabilizing agents and pharmaceutically acceptable carriers. For aerosol administration, the pharmaceutical compositions are generally supplied in finely divided form along with a surfactant and propellant. The surfactant must, of course, be nontoxic, and is generally soluble in the propellant. Representative of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride. Mixed esters, such as mixed or natural glycerides may be employed. A carrier can also be included, as desired, as with, e.g., lecithin for intranasal delivery. For suppositories, traditional binders and carriers may include, for example, polyalkalene glycols or triglycerides. ln a preferred embodiment, the composition or agent of the present invention is prepared for oral, sublingual, buccal, intranasal, intravenous, intramuscular, intraperitoneal and/or inhalation-mediated administration.

Administration

ln a preferred embodiment, the composition or agent of the present invention is administered continuously or discontinuously. For example, the patient may be administered the composition or agent via continuous intravenous infusion or the patient may be administered the composition or agent through several discrete injections. In a preferred embodiment, the agent with 5-HT6R antagonistic activity, and the agent with 5-HT3R antagonistic activity are administered together or separately.

In a preferred embodiment, the composition or agent of the present invention is administered intravenously, intraperitoneally or via inhalation. Where the composition or agent is administered via inhalation, the composition or agent may be aerosolized and administered via an, for example, an anesthesia mask.

In a preferred embodiment, the composition or agent of the present invention is administered intravenously, subcutaneously, orally or via inhalation.

Kit

In a fourth aspect, the present invention provides a kit comprising one or more agent(s) that has or have 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity, and a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent and/or a pharmaceutically acceptable excipient for use in the manufacture of an anti-psychotic and/or a medicament for the treatment and/or prevention of schizophrenia.

The one or more agent(s) that has or have 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity may be any one of the agents discussed in the present document.

The pharmaceutically acceptable carrier, pharmaceutically acceptable diluent and/or pharmaceutically acceptable excipient may be any one of the carriers diluents and excipients already discussed in the present document.

The kit may be used to prepare a liquid, gaseous or solid pharmaceutical composition as already discussed in the present document.

Items

In some embodiments, the present invention provides the following items:

[1] A composition comprising one or more agent(s) for use in the treatment and/or prevention of psychosis and/or schizophrenia,

wherein the one or more agent(s) has or have 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity. [2] The composition for use according to [1], wherein the composition treats and/or prevents psychosis in an individual or animal who suffers from schizophrenia.

[3] The composition for use according to any one of [1] to [2], wherein the composition comprises an agent with 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity.

[4] The composition for use according to any one of [1] to [2], wherein the composition comprises a first agent with 5-HT6 receptor antagonist activity and a second agent with 5-HT3 receptor antagonist activity.

[5] The composition for use according to [3], wherein the agent is a compound according to Formula (I):

wherein:

R¹, R² independently represent hydrogen, an unsubstituted alkyl(Ci-C3) group, an alkyl(Ci-C3) group substituted with one or more halogen atoms or an alkoxyl(Ci-C3) group, or independently a group selected from: cyano, nitro, amino or hydroxyl;

R⁴ represents CO, CH₂, substituted alkyl(Ci-C2) group, SO or S0₂;

R⁵ represents an (i) unsubstituted or substituted aryl (5-6 membered), (ii) unsubstituted or substituted biaryl (8-10 membered), (iii) unsubstituted or substituted heteroaryl (5-6 membered) having 1 -3 heteroatoms independently selected from the group consisting of N, O and S, or (iv) unsubstituted or substituted hetero-biaryl (8-10 membered) having 1-3 heteroatoms independently selected from the group consisting of N, O and S, wherein, optionally the substituted aryl, biaryl, heteroaryl or hetero biaryl is substituted with one or more substituents selected from an alkyl(Ci-C4) group, alkyl(Ci-C3) group substituted with one or more halogen atoms, alkoxy(Ci-C3) group, alkenyl(C₂-C4), halogen, nitro, hydroxyl, cyano, amino, alkylamino or carboxamide; and

R³ represents a substituent consisting of Formula (11):

wherein:

A represents NH, O, CH₂ or NR⁶; R⁶ is an alkyl(Ci-C3) group, benzyl or a carboxyl(Ci-C3) group substituted with an alkyl(Ci-C4) group; m is selected from 0, 1 or 2; and

n is selected from 0, 1 or 2; or

a tautomer, stereoisomer, A-oxide, isotopically-labeled analogue, pharmaceutically acceptable salt, hydrate or solvate thereof.

[6] The composition for use according to [4], wherein the first agent is selected from a list consisting of SB-271046, SB-357134, SB-399885, Ro04-6790, Ro65-7l99, AVN-211, idalopirdine, MS-245, PF-05212365, PRX-07034, SB-742457, R-1485, PF-5212377, Cerlapirdine, SUVN-502, SYN-120, AVN-101, AVN-397, AVN-457, AVN-458, AVN-492, AVN-322, ABT-354, BVT-5182, BVT-74316, J J-39269646, MEM-68626, Ro-4368554, ADN-5127, ADN-0965, ADN-1184, ADN- 2013 and ADN-3662;

and the second agent is selected from a list consisting of vabicaserin, ondansetron, tropisetron, granisetron, dolasetron, palonosetron, ramosetron, cilansetron, vortioxetine, alsoetron DAU 6215, GF038032F, WAY 100289, TAK-058, R3487/MEM3454 and EVP-5141.

[7] The composition for use according to [6], wherein the first agent and second agent are ondansetron and SB-399885;

[8] The composition for use according to [5], wherein the agent is selected from the list consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 and 52 of Table 1.

[9] The composition for use according to any one of [1] to [8], wherein the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent and/or a pharmaceutically acceptable excipient.

[10] The composition for use according to any one of [1] to [7], wherein the composition is prepared for oral, sublingual, buccal, intranasal, intravenous, intramuscular, intraperitoneal and/or inhalation-mediated administration.

[11] The composition for use according to any one of [1] to [10], wherein the composition is administered continuously or discontinuously.

[12] The composition for use according to any one of [1] to [11], wherein the composition is administered intravenously, subcutaneously, orally or via inhalation. [13] A kit comprising :

(i) one or more agent(s) that has or have 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity; and

(ii) a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent and/or a pharmaceutically acceptable excipient,

for use in the manufacture of an anti-psychotic and/or a medicament for the treatment and/or prevention of schizophrenia.

[14] An agent with 5-HT6 receptor antagonist activity for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the agent is co-administered with a second agent and the second agent has 5-HT3 receptor antagonist activity.

[15] An agent with 5-HT3 receptor antagonist activity for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the agent is co-administered with a second agent and the second agent has 5-HT6 receptor antagonist activity.

Examples

Example 1A: In vitro characterization of Compound 6 of Table 1.

In vitro characterization of compound 6 was performed by Euroscreen S.A. (a business unit of Ogeda). Radioligand binding assays were employed for determining the affinity and the selectivity profile of compound 6 for a battery of receptors of 93 primary molecular targets including 13 enzymes, 80 binding assays and CYP profile.

Methods employed in the study were adapted from the scientific literature to maximize reliability and reproducibility. Reference standards were run as an integral part of each assay to ensure the validity of the results obtained. Assays were performed under conditions described in the "Methods" section below.

IC₅₀ values were determined by a non-linear, least squares regression analysis using MathlQTM (ID Business Solutions Ltd., UK). Where inhibition constants (K_;) are presented, the K_; values were calculated using the equation of Cheng and Prusoff (Cheng & Prusoff, 1973. Biochem Pharmacol. 22:3099-3108) using the observed IC₅o of the tested compound, the concentration of radioligand employed in the assay, and the historical values for the K_D of the ligand (obtained experimentally at Eurofins Panlabs, Inc.). Where presented, the Hill coefficient (n_H), defining the slope of the competitive binding curve, was calculated using MathlQTM. Hill coefficients significantly different than a value of 1.0 may suggest that the binding displacement does not follow the laws of mass action with a single binding site.

Methods:

■ 271910 Serotonin (5-Hydroxytryptamine) S-HTa

Source: Huma t HEK-293 cells Ligand: 0 69 nM pH] GR-65630

Vehicle: i 00% Non-Specific Ligand: 10 0 mM MDL 72222

Incubation Time/Temp: 60 min Specific Binding: 90% *

Incubation Buffer: 50 mM 74, 1 mM EDTA, Quantitation Method: Radioligand Binding

5 mM

Kd: 0.20 n

Significance Criteria: >50% of max stimulation or inhibition

Brmax: 11 0 pmole/mg Protein *

271910 Boess F6, Steward LJ, Steele JA, Liu D, Reid J, Glencorse TA and Martin IL (1987)

Analysis of the ligand binding site of the 5-HT ₃ receptor using site directed mutagenesis: importance of glutamate 106 Neuropharmacology 36(4-5): 637-647

Miller K, Welsberg E, Fletcher PW and Teller M (1992)

Membrane-bound and solubilized brain 5-HT; receptors improved radioligand binding assays using bovine area postrema or rat cortex and the radioligands ⁵H-GR66630 ⁵H-BR143694 and’H-LY278684 Synapse 11( 1 ) 58-66

■ 271650 Serotonin (5-Hydroxytryptamine) 5-HΪ2A

Source: Human recombinant CHO-K1 cells Ligand: 0.50 nM pH] Ketan serin

Vehicle: 1 00% DMSO Non-Specific Ligand: 1 0 pM Mianserin

Incubation Time/Temp: 60 minutes @ 25°C Specific Binding: 90% *

Incubation Buffer: 50 mM Tris-HCI, pH 74 Quantitation Method: Radioligand Binding

Kd: 0 20 nM * Significance Criteria: >50% of max stimulation or inhibition

Bmax: 0 51 pmole/mg Protein *

271650 Bonhaus DW, Bach C, DeSouza A, Salazar FHR, Matsuoka BD, Zuppan P, Chan HW and Eglen RM

(1995)

i

■ 204110 Adrenergic bi

Source: Human recombinant CHQ cells Ligand: 0 20 nM pH] CGP-12177

Vehicle: 1 00% DMSO Non-Specific Ligand: 10 0 mM !CI-118551

Incubation Time/Temp: 60 minutes @ 25°C Specific Binding: 95% *

Incubation Buffer: 50 mM Tris-HCI, pH 7 4, 0.5 mM Quantitation Method: Radioligand Binding

EDTA, 5 0 mM MgCb, 120 mM NaCI

Kd: 044 nM * Significance Criteria: >50% of max stimulation or inhibition

Bmax: 0 44 pmole/mg Protein *

204110 McCrea KE and Hill S3 (1993)

Salmeterol a long-acting pi-adrenoceptor agonist mediating cyclic AMP accumulation in a neuronal cell line Br J Pharmacol HO 619-626

■ 203630 Adrenergic am

Source: Human recombinant CHO-K1 cells Ligand: 1.50 nM pH] Rauwolsdne

Vehicle: 1 00% DMSO Non-Specific Ligand: 10 0 mM WB-4101

Incubation Time/Temp: 60 minutes @ 25°C Specific Binding: 95% *

Incubation Buffer: 50 mM Tris-HCI, pH 7.4, 1 mM EDTA Quantitation Method: Radioligand Binding

Kd: 1 50 nM * Significance Criteria: >50% of max stimulation or inhibition

Bmax: 16 0 pmole/mg Protein * 203630 Gleason MM and Hiebie JP (1991)

Ability of SK8F 104078 and SK&F 104856 to identify alpha-2 adrenoceptor subtypes in NCB20 cells and guinea pig lung J Pharmacol Exp Ther 259(31: 1 124-1132

Lalchandani SG, Lei L, Zheng W, Suni MM. Moore BM, Liggett SB, Miller DD and Feller DR (2002)

Yohimbine dimers exhibiting selectivity for the human alpha 2C-adrenoceptor subtype J Pharmacol Exp Ther 303(31:

979-984

■ 204010 Adrenergic bi

204010 Feve S, Elhadri K, Quignard-Boulange A and Pairault J (1994)

Transcriptional down-regulation by insulin of the Ps-adrenergic receptor expression in 3T3-F442A adipocytes: A mechanism for repressing the cAMP signalling pathway. Proc Natl Acad Sci U S A. 91: 5877-5681.

■ 271700 Serotonin (5-Hydroxytryptamine) 5-HΪ2B

271700 Bonhaus DW, Bach C, DeSouza A, Salazar FHR, Matsuoka BD, Zuppan P, Chan HW and Eglen RM

219500 Dearry A, Gingrich JA, Faiardeau P, Fremeau Jr RT, Bates MD and Caron MG (1990)

Molecular cloning and expression of the gene for a human Qt dopamine receptor. Nature 347(62883:72-76

Zhou Q-Y, Grandy DK, Thambl L, Kushner JA, Van Tol HHM, Cone R, Pribnow D, Salon J, Bunzow JR and Civelli O (1990)

Cloning and expression of human and rat Di dopamine receptors Nature 347(62883:76-80.

■ 219600 Dopamine D2L

Source: Human recombinant CHO cells Ligand: 0.16 nM [³H] Spiperone

Vehicle: 100% DMSO Non-Specific Ligand: 10.0 mM Haloperidoi

Incubation Time/Temp: 2 hours @ 25°C Specific Binding: 85% *

Incubation Buffer: 50 mM Tris-HCI, pH 7.4, 1.4 mM Quantitation Method: Radioligand Binding

Ascorbic Acid, 0.001% BSA, 150 mM

NaCI

Kd: 0.080 nM * Significance Criteria: >50% of max stimulation or inhibition

Bmax: 0.48 pmole/mg Protein * 219600 Grandy DK, Marchionni MA, Makam H, Stofko RE, Aifano M, Frothingham L, Fishcer JB, Burke-Howe KJ, Bunzow JR, Server AC and Civeili O (198®)

Cloning of the cDNA and gene for a human Dr dopamine receptor Proc Natl Acad Sci USA. 86{24):9762-9766.

Hayes G. Biden TJ. Selbie LA and Shine J (1992)

Structural subtypes of the dopamine receptor are functionally distinct Expression of the cloned D;> and D;e subtypes in a heterologous cell line Mol Endocrinol 6(6) 920-926

■ 219700 Dopamine Dis

219700 Grandy OK, Marchionni MA, Makam H, Stofko RE, Aifano M, Frothingham L, Fischer JB, Burke- Howie KJ, Bunzow JR, Server AC and Civeili O (1989)

Cloning of the cDNA and gene for a human Da dopamine receptor Proc Natl Acad Sci USA. 86(24):9762-9766.

Hayes G, Biden TJ, Selbie LA and Shine J (1992)

■ 219800 Dopamine Da

Source: Human recombinant CHO cells Ligand: 0 70 nM pH] Spiperone

Vehicle: 1 00% DMSO Non-Specific Ligand: 25 0 mM S(-)-Sulpiride incubation Time/Temp: 2 hours @ 37°C Specific Binding: 85% *

incubation Buffer: 50 mM Tris-HCi. pH 7.4, 1 4 mM Quantitation Method: Radioligand Binding

Ascorbic Acid. 0 001% BSA, 150 mM

MaCi

Kd: 0 36 nM * Significance Criteria: >50% of max stimulation or inhibition

Bmax: 1 10 pmole/mg Protein *

2 : 9800 Sokoloff P. Giros B, Martres M-P. Bouthenet -L and Schwartz J-C (1990}

239610 De Backer MD, Gommeren W, Moereels H, Nobels G, Van Gompel P, Leysen JE and Luyten WH

■ 271 1 10 Serotonin (5-Hydroxytryptamine) 5-HTm

271110 Martin GR and Humphrey PPA (1994)

Receptor for 5-hydroxytryptamine current perspectives on classification and nomenclature Neuropharmacot 33(3-4) 261-

273

May JA. McLaughlin MA. Sharif NA. Heliberg MR and Dean TR (2003)

Evaluation of the ocular hypotensive response of serotonin 5-HT- and 5-HT: receptor ligands in conscious ocular hypertensive cynomolgus monkeys 2 Pharmacol Exp Trier 306, 1 i 301 -309

■ 214600 Calcium Channel L-Type. Dihydropyridine

Source: Wistar Rat cerebral cortex Ligand: 0.10 nM [¾] Nitrendipine

Vehicle: I OO°o DMSO Non-Specific Ligand: 1 0 mM Nitrendipine

Incubation Timefiemp: 90 minutes @ 25^CC Specific Binding: 91%‘

Incubation Buffer: 50 mM Tris-HCI, pH 74 Quantitation Method: Radiokiand Binding

Kd: 0 18 nM * Significance Criteria: 50% of max stimulation or inhibition

Bmax: 0 23 pmole/mg Protein‘

214600 Ehlert F«J, Roeske WR, Itoga E and Yamamura HI (1982)

The binding of pHJnitrendipine to receptors for calcium channel antagonists in the heart, cerebral cortex, and ileum of rats Life Sci 30(25):2191-2202.

Gould RJ, Murphy KMM and Snyder SH (1982)

pHJnitrendipine-Iabeled calcium channels discriminate inorganic calcium agonists and antagonists Proc Natl Acad Sci USA 79(11):3656- 3660.

■ 279510 Sodium Channel, Site 2

Source: Wistar Ra Ligand: 5 0 nM [³H] Batrachotoxinin

Vehicle: 1 00% D Non-Specific Ligand: 100 mM Veratridine

Incubation Time/Temp: 60 minute Specific Binding: 77% *

Incubation Buffer: 50 mM H Quantitation Method: Radioligand Binding

7 4 130

mM KCI,

Glucose,

Kd: 0.052 mM

Significance Criteria: >50% of max stimulation or inhibition

Bmax: 0 70 pmole/mg Protein *

279510 Cattera WA. Morrow CS, Daly JW and Brown CB (1981)

■ 271 800 Serotonin (5-Hydroxytryptamine) 5-HT2C

Source: Human recombinant CHO-K1 cells Ligand: 1 0 nM |³H] Mesulergine

Vehicle: 1 00% DMSO Non-Specific Ligand: 1 0 pM Mianserin

Incubation Time/Temp: 60 minutes @ 25°C Specific Binding: 90% *

Incubation Buffer: 50 mM Tris-HCI, pH 74, 0.1% Quantitation Method: Radioligand Binding

Ascorbic Acid 10 mM Pargylme

Kd: 1 10 nM ' Significance Criteria: >50% of max stimulation or inhibition

Bmax: 4 90 pmole/mg Protein *

271800 Wolf

The se

serotomn-mediated phosphomosttide hydrolysis J Neurochem 69(4) 1449- 1458

■ 271230 Serotonin ( 5-Hydroxytryptamine) 5-HTIB

Source: Human recombinant Ctiem-1 cells Ligand: 1.0 nM pH] GR125743

Vehicle: 1 00% DMSO Non-Specific Ligand: 10 0 mM Serotonin (5-HT)

Incubation Time/Temp: 90 minutes @ 37'C Specific Binding: 90% *

Incubation Buffer: 50 mM Tris-HCI, pH 7 4, 1 mM EDTA, Quantitation Method: Radioligand Binding

10 mM MgCI;

Kd: 3 20 nM * Significance Criteria: >50% of max stimulation or inhibition

Bmax: 22 0 pmole/mg Protein‘ 271230 Maier DL, Sobotka-Briner C, Ding M, Powell ME, Jiang Q, Hill G, Heys JR, Elmore CS, Pierson ME and Mrzljak L (2009)

[N-niethyl-3H3]AZ t0419369 binding to the 5-HT1B receptor in vitro characterization and in vivo receptor occupancy. J Pharmacol Exp Ther 330) 17342-351

Xie Z, Lee SP, O'Dowd BF and George SR (1999)

Serotonin S-HT·- and 5-BT n receptors form homodimers when expressed alone and heterodimers when co-expressed. FEBS Lett 456(1 > 63-67

■ 265300 Potassium Channel hERG

Source: Human recombinant HEK-293 cells Ligand: 1 50 nM pH] Astern izole

Vehicle: 1 00% DMSO Non-Specific Ligand: 10 0 mM Astemizole

Incubation Time/Temp: 60 minutes @ 25"C Specific Binding: 90% *

Incubation Buffer: 10 mM HEPES. pH 7 4 0 l°o BSA, 5 Quantitation Method: Radioligand Binding

mM KCI. 0 8 mM MgCI; 130 mM

NaCI. 1 mM EGTA, 10 M Glucose

Kd: 6 80 nM * Significance Criteria: >50% of max stimulation or inhibition

Bmax: 6 30 pmole/mg Protein *

;65S:c Fin!ayson K, Turnbull L, January CT, Sharkey J and Kelly JS (2001)

pHjdofetilide binding to HERG transfected membranes a potential high throughput preclimcal screen Eur J Pharmacol. 430(1 ) 147- 148

Zhou Z, Gong Q, Ye B, Fan Z, Makielski JC. Robertson GA and January CT {1998}

Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature Biophys J

74( ! ):230-241

■ 214510 Calcium Channel L-Type, Benzothiazepine

Source: Wistar Rat brain Ligand: 2 0 nM [³H] Diitiazem

Vehicle: 1 00% DMSO Non-Specific Ligand: 10 0 mM Diitiazem

Incubation Time/Temp: 3 hours @ 4°C Specific Binding: 73% *

Incubation Buffer: 50 mM Tris-HCI, pH 7 4, 0 1% BSA Quantitation Method: Radioligand Binding

Kd: 16.0 nM * Significance Criteria: >50% of max stimulation or inhibition

Bmax: 0 21 pmole/mg Protein *

214510 Schoemaker H and Langer SZ {1985}

pHJDi!tiazem binding to calcium channel antagonists recognition sites in rat cerebral cortex Eur J Pharmacol 111(2):273- 277.

■ 220320 Transporter, Dopamine (DAT)

Source: Human recombinant CHO-S cells Ligand: 0 15 nM [¹²⁵i] RTI-55

Vehicle: 1 00% DMSO Non-Specific Ligand: 10 0 mM Nomifensine

Incubation Time/Temp: 3 hours @ 4°C Specific Binding: 90% *

Incubation Buffer: 50 mM Tris-HCI, pH 7 4, 100 mM Quantitation Method: Radioligand Binding

NaCI, I mM Leupeptin, 10 pM PMSF

Kd: 0 58 nM ^* Significance Criteria: >50% of max stimulation or inhibition

Bmax: 0 047 pmole/mg Protein *

220320 Glros B and Caron MG (1993)

Molecular characterization of the dopamine transporter. Trends Pharmacol Sci. 14(2): 43-49.

Gu H, Wall SC and Rudnick G (1994)

Stable expression of biogenic amine transporters reveals differences m inhibitor sensitivity kinetics and ion dependence J Bio! Chem 269{ !Q} 7 124-7 130

■ 204410 Transporter, Norepinephrine (NET)

Source: Human recombinant MDCK cells Ligand: 0 20 nM f ²⁵I] RTI-55

Vehicle: 1 00% DMSO Non-Specific Ligand: 10.0 mM Desipramine

Incubation Time/Temp: 3 hours @ 4°C Specific Binding: 75% ^*

Incubation Buffer: 50 mM Tris-HCI, pH 7 4, 100 M Quantitation Method: Radioligand Binding

NaCI, 1 mM Leupeptin, 10 pM PMSF

Kd: 0.024 mM * Significance Criteria: z50 of max stimulation or inhibition

Bmax: 2 50 pmole/mg Protein ' 204410

■ 215000 Calcium Channel L-Type, Phenylalkylamine

Source: Wistar Rat brain Ligand: 0.40 nM pH] (-}-Desmethoxyverapami!

(D-888)

Vehicle: 1 00% DMSQ Non-Specific Ligand: 10 0 mM Methoxyverapamil (0-600)

Incubation Time/Temp: 60 minutes @ 25°C Specific Binding: 80% *

Incubation Buffer: 50 mM HEPES, pH 7 4 Quantitation Method: Radioligand Binding

Kd: 14 0 nM * Significance Criteria: >50% of max stimulation or inhibition

Bmax: 1 60 pmoie/mg Protein *

: ^:o; Reynolds IJ. Snowman AM and Snyder SH (1986)

(-(-[^'’HJDesmefhoxyverapami! labels multiple calcium channel modulator receptors in brain and skeletal muscle membranes Differentiation by temperature and dihydropyndmes J Pharmacol Exp Ther 237 73 f -738

■ 252610 Muscarinic Mi

Source: Human recombinant CHO-K1 cells Ligand: 0.80 nM pH] N-Methylscopolamine

Vehicle: 1.00% DMSO Non-Specific Ligand: 1 0 pM Atropine

Incubation Time/Temp: 2 hours @ 25°C Specific Binding: 95% *

Incubation Buffer: 50 mM Tris-HCI, pH 7 4, 10 M Quantitation Method: Radioligand Binding

MgCI:, 1 mM EDTA

Kd: 0.26 nM * Significance Criteria: >50% of max stimulation or inhibition

Bmax: 2 0 pmole/mg Protein *

252610 Buckley NJ, Bonner Tl, Buckley CM and Brann MR (1989)

Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 ceils. Mol Pharmacol 35(4): 469- 476

Luthin GR and Wolfe BB (1984)

Comparison of pHJpirenzepine and (^:'H]quinuciidinylbenaiate binding to muscarine cholinergic receptors in rat brain J Pharmacol Exp Ther 228(3) 648-655

■ 272100 Serotonin (5-Hydroxytryptamine) 5-HTBA

272100 Rees S, den Daas I, roord S, Goodson S, Bull D, Kilpatriele G and Lee M (1994)

Cloning and characterization of the human S-BT« serotonin receptor. FEBS Let. 355:242-246.

■ 272320 Serotonin (Sj-Hydroxytryptamine) 5-HTT

Source: Human recombinant CHO-K1 cells Ligand: 5 50 nM [³H] Lysergic acid diethylamide

(LSD)

Vehicle: 1 00% DMSQ Non-Specific Ligand: 10 0 mM Serotonin (5-HT)

Incubation Time/Temp: 2 hours @ 25°C Specific Binding: 90% *

Incubation Buffer: 50 mM Tris-HCI, pH 7 4, 10 mM Quantitation Method: Radioligand Binding

MgCb 0 5 mM EDTA

Kd: 7 40 nM‘ Significance Criteria: >50% of max stimulation or inhibition

Bmax: 0 95 pmole/mg Protein * 272320 Roth BL, Cralgo SC, Choudhary MS, Uluer S, Monsma Jr FJ, Shen Y, Meltzer HY and Sibley DR

Shen Y, Monsma Jr FJ. Metcalf MA. Jose PA, Hamblin MW and Sibley DR (1993)

Molecular cloning and expression of a 5-hydroxytryptamine 7 serotonin receptor subtype J Biol Chem 268: 18200 - 18204.

■ 260410 Opiate m(OR3, MOP)

Bmax: 3 80 pmole/mg Protein *

260410 Wang Ji, Johnson PS, Perslco AM, Hawkins AL, Griffin CA and Uhl GR (1994)

Human mu opiate receptor: cDNA and genomic clones, pharmacologic characterization and chromosomal assignment. FEBS Lett. 338:217-222.

■ 260210 Opiate K(OP2, KOP)

Source: Human recombinant HEK-293 cells Ligand: 0 60 nM pH] Diprenorphine

Vehicle: 1.00% DMSO Non-Specific Ligand: 10.0 mM Naloxone

Incubation Time/Temp: 60 minutes (<¾ 25‘C Specific Binding: 9ϋ% ^'

Incubation Buffer: 50 mM Tris-HCI, pH 7.4 Quantitation Method: Radiotgand Binding

Kd: 0 40 nM * Significance Criteria: >50% of max stimulation or inhibition

Bmax: 1 10 pmole/mg Protein *

260210 Maguire P, Tsaf N, Kamal J, Cometta-Morini C, Upton C and Loew G (1992)

Pharmacological proles of fentanyl analogs at p, 6, and k opiate receptors. Eur J Pharmacol. 213(2): 219-225.

Simonin F, Gaveriaux-Ruff C, Befort K, Matthes H, Lannes B, Michelet» G, Matel M-G, Charron G,

Bloch B and Kieffer B (1995)

Kappa-opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. Proc Natl Acad Sci USA. 92(15): 7006-7010.

Bmax: 0 71 pmole/mg Protein *

278110 Ganapathy ME, Prasad PD, Huang W, Seth P, Leibach FH and Ganapathy V (19»)

Molecular and ligand-binding characterization of the s-receptor in the Jurkat human T lymphocyte cell line. J Pharmacol

Exp Ther. 289(1): 251-260

■ 203710 Adrenergic Q2B

203710 Uhlen S, Dambrova M, Nasman J, Schioth HB, Gu Y, Wikberg-Matsson A and Wikberg Ji (1998)

[³H]RS79948-197 binding to human, rat, guinea pig and pig a»-, aze- and oac- adrenoceptors comparison with MK912, RX821002, rauwolscine and yohimbine Eur J Pharmacol 343 (1): 93-101. ■ 255520 Tachykinin NKi

ance P g

Kd: 2.10 nM ' Significance Criteria: >50% of max stimulation or inhibition

Bmax: 1 70 pmole/mg Protein *

255520 Patacchini R and Maggi CA. (1995)

Tachykinin receptors and receptor subtypes. Arch Int Pharmacodyn. 329:161-184.

Table 2: Comprehensive pharmacological profile of compound 6 against a panel of receptors

Cat.# Assay Name Species Cone. % Inh.

271910 Serotonin (5-Hydroxytryptamine) 5-HT3 hum 10 nM 76 4.

271650 Serotonin (5-Hydroxytryptamine) 5-HT2A hum 1 mM 80 0.

204110 Adrenergic b2 hum 1 mM 93 0.

203630 Adrenergic a2A hum 1 mM 80 0.

204010 Adrenergic b1 hum 1 mM 75 0.

271700 Serotonin (5-Hydroxytryptamine) 5-HT2B hum 1 mM 71 0.

219800 Dopamine D3 hum 1 mM 63 0.

239610 Histamine H1 hum 1 mM 67 0.

271110 Serotonin (5-Hydroxytryptamine) 5-HT1A hum 1 mM 53 0.

214600 Calcium Channel L-Type, Dihydropyridine rat 1 mM 60 0.

279510 Sodium Channel, Site 2 rat 10 mM 94 0.

271800 Serotonin (5-Hydroxytryptamine) 5-HT2C hum 10 pM 94 1.

271230 Serotonin (5-Hydroxytryptamine) 5-HT 1 B hum 10 pM 90 1.

265900 Potassium Channel hERG hum 10 pM 107 1.

214510 Calcium Channel L-Type, Benzothiazepine rat 10 pM 83 1.

220320 Transporter, Dopamine (DAT) hum 10 pM 101 1.

204410 Transporter, Norepinephrine (NET) hum 10 pM 94 1.

215000 Calcium Channel L-Type, Phenylalkylamine rat 10 pM 78 1.

252610 Muscarinic M1 hum 10 pM 54 7.

272100 Serotonin (5-Hydroxytryptamine) 5-HT5A hum 10 pM 64 5.

272320 Serotonin (5-Hydroxytryptamine) 5-HT7 hum 10 pM 65 5.

260410 Opiate m(OR3, MOP) hum 10 pM 59 7.

260210 Opiate K(OP2, KOP) hum 10 pM 55 8.

278110 Sigma o1 hum 10 pM 51 8.

203710 Adrenergic a2B hum 10 pM 53 10

255520 Tachykinin NK1 hum_ 10 pM 58 1

* A standard error of the mean is presented where results are based on multiple, independent determinations. gp=Guinea pig; ham=Hamster; hum=Human

Table 2 demonstrates that Compound 6 of Table 1 also has 5-HT 3 antagonist activity. WO 2015/012704 Al already demonstrated that Compound 6 has 5-HT 6 antagonist activity (WO

2015/012704 Al: p. 47, Table 1 - see compound 30). Thus, Compound 6 has 5-HT 3 and 5-HT6 antagonist activity.

Furthermore, Compound 6 has the following inhibition of Dopamine Dl, Dopamine D2L, and Dopamine D2S at 10 mM:

Cat.# Assay Name Species Cone. % Inh.

219500 Dopamine D1 hum 10 pM 27

219600 Dopamine D2L hum 10 pM 46

219700 Dopamine D2S hum_ 10 pM 46 Example IB: 5-HT3 Human Serotonin Ion Channel Binding (Antagonist Radioligand) Assay form selected compounds

109. Hope, A.G. et al. (1996), Brit. J. Pharmacol., 118_: 1237-1245.

S41 : (R)-l-((3-chlorophenyl)sulfonyl)-N-(pyrrolidin-3-yl)-lH-pyrrolo[3,2-c]quinolin-4-amine S42 : (S)-l-((3 -chlorophenyl)sulfonyl)-N-(pyrrolidin-3-yl)- 1 H-pyrrolo [3,2-c] quinolin-4-amine S54: 4-(l-((3-chlorophenyl)sulfonyl)-lH-pyrrolo[3,2-c]quinolin-4-yl)morpholine

S41 , S42, and S54 are compounds encompassed by WO 2015/012704 Al. Thus, it is shown in this Example that not all compounds disclosed in WO 2015/012704 Al are dual antagonists.

Example 2: Effects of 5-HT_j and 5-HTg R antagonists on PCP-induced disruption of cortical activity In order to assess the ability of Compound 6 of Table 1 to counteract phencyclidine (PCP) effects on low frequency oscillations (LFO), similar experiments as previously described (Llado-Pelfort et al., 2016. Eur. Neuropsychopharmacol. 26(3):6l4-625; van den Munkhof et al., 2017. Eur Neuropsychopharmacol. 27(12):1248-1257) were performed in chloral hydrate-anesthetized rats, examining the effects of Compound 6 (3 mg/kg free base, i.v.) after PCP (0.25-0.5 mg/kg i.v.). Experiments were carried out in the medial prefrontal cortex (mPFC).

In this protocol, in brief, rats were anesthetized (chloral hydrate 400 mg/kg i.p.) and positioned in a stereotaxic apparatus. Thereafter, chloral hydrate was continuously administered i.p. at a dose of 50-70 mg/kg-h using a perfusion pump. Body temperature was maintained at 37 °C throughout the experiment with a heating pad. All wound margins and points of contact between the animal and the stereotaxic apparatus were infiltrated with lidocaine solution (5%). In order to minimize pulsation, the atlanto- occipital membrane was punctured to release some CSF. Local field potential was amplified with a Neurodata IR283 (Cygnus Technology Inc., Delaware Water Gap, PA), postamplified and filtered with a Cibertec amplifier (Madrid, Spain) and computed on-line using a DAT 1401 plus interface system Spike2 software (Cambridge Electronic Design, Cambridge, UK). Basal activity was recorded for 5 min and then, PCP (0.25 mg/kg) was administered intravenously. Testing drug was only administered if PCP induced a 30 % reduction of LFO. A second PCP dose (0.25 mg/kg) was administered when a single dose had no effect.

Experimental groups

Experimental groups

1) PCP+ Compound 6 (3.0 mg/kg free base in saline, iv., pH=3) (n=7-8)

2) PCP+ SB-399885 (10 mg/kg free base in 1% aqueous solution of Tween 80, iv) (n=7-8)

3) PCP+ ondansetron (1.28 mg/kg free base in saline, iv) (n=7-8)

4) PCP+ ondansetron + SB-399885 (n=7-8)

Results:

Compound 6 reverts the PCP-disturbed power of low frequency (LFO, 0.1-4 Hz) in the mPFC of anesthetized rats (Fig. 1). This effect is also reversed by classical (haloperidol, chlorpromazine, perphenazine) and atypical (clozapine, olanzapine ...) antipsychotic drugs and not by antidepressant drugs like citalopram. Similar effect, although less robust, is attained by simultaneous administration of the 5-HT3R antagonist Ondansetron and the 5-HT6R antagonist SB-399885 (Fig. 4). This effect was not achieved when Ondansetron and SB-399885 were administered on their own (Fig.2-3).

Example 3: Effect of 5-HT_j and 5-HTg R antagonists on the oscillatory activity in conscious rats

Rats were implanted with Plastics One electrodes (Virgina, USA) under isoflurane anesthesia (induction: 5% isoflurane, O 0.6%; maintenance: 2-3 % isoflurane, O 0.6%). Animals were pretreated (30 minutes before anesthesia inhalation) with an analgesic (Buprenorfme: 0.05 mg/kg s.c.).

Stereotaxic coordinates were taken from bregma and brain surface (mm) according to the rat brain atlas: (Paxinos and Watson, 2005) medial prefrontal cortex (mPFC) AP + 3.4, L-0.7, DV-2.1; Nucleus accumbens (NAc) AP+1.7, L-1.6, DV-6.8; ventral HPC (vHPC) (AP-5.3, L-6.0, DV-6.0). A ground screw and three stabilizer screws were also implanted. The implant is fixed with dental cement.

Buprenorfme (0.05 mg/kg s.c.) and a prophylactic antibiotic (Enrofloxacina 7.5 mg/kg s.c.) was given during 2-3 consecutive days after surgery.

Recordings were made in an open-field consisting of a metal box (50 cm x 50 cm x 40 cm height) placed inside a larger noise-isolated box. Recordings were performed with a digital Lynx system and Cheetah software (Neuralynx, Montana, USA) using an electrical swivel (also from Neuralynx) to allow multiple electrode recording during rat movement. The signal was obtained at 3.2kHz sampling rate and filtered between 0.1 and lOOHz. All recordings were posteriorly downsampled 10 times before analysis. Recordings were made once a week starting one week after surgery. All rats were habituated to the experimental setting for 4-5 days before recordings. On the recording day, drugs (or vehicle) is injected 15-30 minutes after the beginning of the recording.

Data were imported to MATLAB environment (MathWorks, MA, USA) for off-line power and coherence wavelet analysis, using built-in and self-developed routines. The frequency bands analysed were delta (0.2-4Hz), theta (4-lOHz), beta (l0-30Hz) and gamma (30-80Hz).

At the end of recordings, rats were euthanatized by an anesthetic overdose. Histological localization of electrodes was performed by passage of current (intensity: 0.15 mA; duration: 10 s). Brain sections were stained according to standard procedures, to verify recordings sites.

Experimental groups

1) Compound 6 dissolved in a standard isotonic vehicle (3 mg/Kg i.p.) + PCP (2-5 mg/kg i.p.) (n=8)

2) The standard isotonic vehicle + PCP (2-5 mg/kg i.p.) (n=8)

The 3 following areas, PFC, vHPC and NAc, were according to previous literature on 5-HT6 and 5- HT3R expression (East et al., 2002. Synapse. 45(3): 191-9; Helboe et al., 2015. Neuroscience. 310:442-54; Herrik et al., 2016. Neuropharmacology. 107:351-363; Morales & Wang, 2002. J Neurosci. 22(15):6732-4l ; Riga et al., 2016 Neuropharmacology., 108:73-81; Riga et al., 2017 Neuropharmacology .113 (Pt A):l48-l55.

Results:

Compound 6 prevents the increase in power of gamma and fast oscillations induced by PCP in awake animals in key brain areas involved in behavior control, addiction, cognition and executive function, thereby acting as a potential antipsychotic (Fig. 5).

Claims

Claims

1. A composition comprising a first agent that has 5-HT6 receptor antagonist activity and a second agent that has 5-HT3 receptor antagonist activity for use in the treatment and/or prevention of psychosis and/or schizophrenia, wherein

i. the first agent has an 1C50 for the D2 receptor at least 10 times higher than the 1C50 for the 5-HT6 receptor,

ii. the second agent has an 1C50 for the D2 receptor at least 10 times higher than the 1C50 for the 5-HT3 receptor, and

iii. the first and second agent may be the same or different agents.

2. The composition for use according to claim 1, wherein the composition treats and/or prevents psychosis in an individual or animal who suffers from schizophrenia.

3. The composition for use according to any one of claims 1 to 2, wherein the first and second agent are the same agent.

4. The composition for use according to any one of claims 1 to 2, wherein the first and second agents are different agents.

5. The composition for use according to claim 3, wherein the agent is a compound according to Formula (1):

wherein:

R¹, R² independently represent hydrogen, an unsubstituted alkyl(Ci-C3) group, an alkyl(Ci-C3) group substituted with one or more halogen atoms or an alkoxyl(Ci-C3) group, or independently a group selected from: cyano, nitro, amino or hydroxyl;

R⁴ represents CO, CH₂, substituted alkyl(Ci-C2) group, SO or S0₂;

R⁵ represents an (i) unsubstituted or substituted aryl (5-6 membered), (ii) unsubstituted or substituted biaryl (8-10 membered), (iii) unsubstituted or substituted heteroaryl (5-6 membered) having 1-3 heteroatoms independently selected from the group consisting of N, O and S, or (iv) unsubstituted or substituted hetero-biaryl (8-10 membered) having 1-3 heteroatoms independently selected from the group consisting of N, O and S, wherein, optionally the substituted aryl, biaryl, heteroaryl or hetero biaryl is substituted with one or more substituents selected from an alkyl(Ci-C4) group, alkyl(Ci-C3) group substituted with one or more halogen atoms, alkoxy(Ci-C3) group, alkenyl(C2-C4), halogen, nitro, hydroxyl, cyano, amino, alkylamino or carboxamide; and

R³ represents a substituent consisting of Formula (II):

wherein:

A represents NH, O, CH₂ or NR⁶;

R⁶ is an alkyl(Ci-C3) group, benzyl or a carboxyl(Ci-C3) group substituted with an alkyl(Ci-C4) group; m is selected from 0, 1 or 2; and

n is selected from 0, 1 or 2; or

a tautomer, stereoisomer, /V-oxidc, isotopically-labeled analogue, pharmaceutically acceptable salt, hydrate or solvate thereof.

6. The composition for use according to claim 4, wherein the first agent is selected from a list consisting of SB-271046, SB-357134, SB-399885, Ro04-6790, Ro65-7l99, AVN-211, idalopirdine, MS-245, PF-05212365, PRX-07034, SB-742457, R-1485, PF-5212377, Cerlapirdine, SUVN-502, SYN-120, AVN-101, AVN-397, AVN-457, AVN-458, AVN-492, AVN-322, ABT-354, BVT-5182, BVT-74316, JNJ-39269646, MEM-68626, Ro-4368554, ADN-5127, ADN-0965, ADN-1184, ADN- 2013 and ADN-3662;

and the second agent is selected from a list consisting of vabicaserin, ondansetron, tropisetron, granisetron, dolasetron, palonosetron, ramosetron, cilansetron, vortioxetine, alsoetron DAU 6215, GF038032F, WAY 100289, TAK-058, R3487/MEM3454 and EVP-5141.

7. The composition for use according to claim 6, wherein the first agent and second agent are SB-399885 and ondansetron.

8. The composition for use according to claim 5, wherein the agent is selected from the list consisting of compounds l-(phenylsulfonyl)-4-(piperazin-l-yl)-lT/-pyrrolo[3,2-c]quinoline, tert-butyl 4-( 1 -(phcnylsulfonyl)- 1 /7-pyrrolo[3,2-c]quinolin-4-yl)pipcrazinc- 1 -carboxylatc, l-((2- bromophenyl)sulfonyl)-4-(piperazin-l-yl)-l7/-pyrrolo[3,2-c]quinoline, l-((3-chlorophenyl)sulfonyl)- 4-(piperazin-l -yl)- 1 /7-pyrrolo[3,2-c]quinolinc, tert-butyl 4-( 1 -((3-chlomphcnyl)sulfonyl)- 1 H- pyrrolo[3,2-c]quinolin-4-yl)piperazine-l-carboxylate, l-((3-fluorophenyl)sulfonyl)-4-(piperazin-l-yl)- 1 /7-pyiTolo[3,2-c]quinolinc, l-((4-fluorophenyl)sulfonyl)-4- (pipcrazin- 1 -yl)- 1 //-pyrrolo[3,2- c]quinoline, l-((2,5-difluorophenyl)sulfonyl)-4-(piperazin-l-yl)-l7/-pyrrolo[3,2-c]quinoline, 1 -((3,4- difluorophenyl)sulfonyl)-4- (piperazin-l -yl)- 1 7-pyrmlo[3,2-c]quinolinc, 1 -((3,4- dichlorophcnyl)sulfonyl)-4-(pipcrazin- 1 -yl)- 1 7-pyrmlo[3,2-c]quinolinc, 1 -((3-

(trifluoromcthyl)phcnyl)sulfonyl)-4-(pipcrazin- 1 -yl)- 1 /7-pyrrolo[3,2-c]quinolinc, l-((4-

(trifluoromcthyl)phcnyl)sulfonyl)-4-(pipcrazin- 1 -yl)- 1 /7-pyrrolo[3,2-c]quinolinc, 1 -((3- mcthoxyphcnyl)sulfonyl)-4-(pipcrazin- 1 -yl)- 1 /7-pyrrolo[3,2-c]quinolinc, l-((3-cyanophenyl)sulfonyl)- 4-(pipcrazin- 1 -yl)- 1 /7-pyrrolo[3, 2-c] quinoline, 1 -((3-mcthylphcnyl)sulfonyl)-4-(pipcrazin- 1 -yl)- 1 H- pyrrolo [3 ,2-c] quinoline, 1 -((4-isopropylphcnyl)sulfonyl)-4-(pipcrazin- 1 -yl)- 1 //-pyrrolo[3,2- c]quinoline, l-((4-(fert-butyl)phenyl)sulfonyl)-4-(piperazin-l-yl)-li7-pyrrolo[3,2-c]quinoline, l-((4- aminophenyl)sulfonyl)-4-(piperazin-l -yl)-lH-pyrrolo[3,2-c]quinoline, 1 -(naphthalen- l -ylsulfonyl)-4- (piperazin- 1 -yl)- 1 /7-pyrrolo[3,2-c] quinoline, teri-butyl 4-( 1 -(naphthalen- 1 -ylsulfonyl)- 1 //-pyrrolo[3,2- c] quinolin-4-yl)piperazine- 1 -carboxylate, 1 -(naphthalen-2-ylsulfonyl)-4-(piperazin- 1 -yl)- 1 H- pyrrolo [3 ,2-c] quinoline, l-(quinolin-8-ylsulfonyl)-4-(piperazin-l-yl)-li7-pyrrolo[3,2-c]quinoline, 1- ((5-chlorothiophen-2-yl)sulfonyl)-4- (piperazin-l -yl) -li7-pyrrolo[3,2-c]quinoline, feri-butyl 4-(l-((5- chlorothiophen-2-yl)sulfonyl)-lii-pyrrolo[3,2-c]quinolin-4-yl)piperazine-l -carboxylate, l-((5- methylbenzo[/?]thiophen-2-yl)sulfbnyl)-4-(piperazin-l-yl)-li7-pyrrolo[3,2-c]quinoline, l-((5-chloro-3- methylbenzo[/?]thiophen-2-yl)sulfonyl)-4-(piperazin-l-yl)-li7-pyrrolo[3,2-c]quinoline, teri-butyl 4-(l- ((5-chloro-3-mcthylbcnzo[/ ]thiophcn-2-yl)sulfonyl)- 1 /7-pyrrolo[3,2-c]quinolin-4-yl)pipcrazinc- 1 - carboxylate, l-(3-chlorobenzyl)-4-(piperazin-l-yl)-lii-pyrrolo[3,2-c]quinoline, l -(3-fluorobenzyl)-4- (pipcrazin- 1 -yl)- 1 /7-pyrrolo[3,2-c]quinolinc, (3-chlomphcnyl)-(4-(pipcrazin- 1 -yl)- 1 7-pyrmlo[3,2- c] quinolin- 1 -yl)methanone, (3 -methylphenyl)-(4-(piperazin- 1 -yl)- 1 //-pyrrolo[3,2-c] quinolin- 1 - yl)methanone, 1 -(phcnylsulfonyl)-4-(4-mcthylpipcrazin- 1 -yl)- 1 /7-pyrrolo[3,2-c]quinolinc, l-((3- chlorophenyl)sulfonyl)-4-(4-methylpiperazin-l -yl)-li7-pyrrolo[3,2-c]quinoline, l-((3- fluoiOphcnyl)sulfonyl)-4-(4-mcthylpipcrazin- 1 -yl)- 1 /7-pyrrolo[3,2-c]quinolinc, l-((4- fluorophenyl)sulfonyl)-4-(4-methylpiperazin-l -yl)-lii-pyrrolo[3,2-c]quinoline, l-((4- aminophenyl)sulfonyl)-4-(4-methylpiperazin- 1 -yl)- 1 //-pyrrolo [3 ,2-c] quinoline, 1 -(naphthalen- 1 - ylsulfonyl)-4-(4-mcthylpipcrazin- 1 -yl)- 1 /7-pyrrolo[3,2-c]quinolinc, l -(quinolin-8-ylsulfonyl)-4-(4- mcthylpipcrazin- 1 -yl)- 1 //-pyrrolo[3,2-c]quinolinc, 1 -(phcnylsulfonyl)-4-(4-bcnzylpipcrazin- 1 -yl)- 1 H- pyrrolo [3 ,2-c] quinoline, 1 -((5-chlorothiophcn-2-yl)sulfonyl)-4-(4-bcnzylpipcrazin- 1 -yl)- 1 H- pyrrolo [3 ,2-c] quinoline, 1 -(quinolin-8-ylsulfonyl)-4-(4-bcnzylpipcrazin- 1 -yl)- 1 /7-pyrrolo[3,2- c]quinoline, 8-nitro-l-((4-isopropylphenyl)sulfonyl)- 4-(piperazin-l -yl)-lii-pyrrolo[3,2-c]quinoline, 8-nitro-l-((3-(trifluoromethyl)phenyl)sulfonyl)-4-(piperazin-l-yl)-lii-pyrrolo[3,2-c]quinoline, 8- amino-l-((3,4-dichlorophenyl)sulfonyl)-4-(piperazin-l-yl)-lii-pyrrolo[3,2-c]quinoline, 8-cyano-l-(3- mcthylphcnyl)-4-(pipcrazin- 1 -yl)- 1 //-pyrrolo[3,2-c]quinolinc, 8-cyano-l -(naphthalen- 1 -ylsulfonyl)-4- (piperazin- 1 -yl)- 1 /7-pyrrolo[3,2-c] quinoline, 8-methoxy- 1 -((3-(trifluoromethyl)phenyl)sulfonyl)-4-

(pipcrazin- 1 -yl)- 1 /7-pyrrolo[3,2-c]quinolinc, 8-methoxy-l-((3-fluorophenyl)sulfonyl)-4-(piperazin-l- yl)-lii-pyrrolo[3,2-c]quinoline, 8-chlom- 1 -((3-chloiOphcnyl)sulfonyl)-4-(pipcrazin- 1 -yl)- 1 H- pyrrolo[3,2-c]quinoline, 8-chlom- 1 -(naphthalen- 1 -ylsulfonyl)-4-(pipcrazin- 1 -yl)- 1 7-pyrmlo[3,2- c] quinoline, 7-fluoro- 1 -((3 -methylphenyl)sulfonyl)-4-(piperazin- 1 -yl)- 1 7-pyrmlo [3 ,2-c] quinoline, and 7-fluoro- 1 -((3-chlorophcnyl)sulfonyl)-4-(pipcrazin- 1 -yl)- 1 7-pyrrolo[3,2-c]quinolinc.

9. The composition for use according to any one of claims 1 to 8, wherein the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent and/or a pharmaceutically acceptable excipient.

10. The composition for use according to any one of claims 1 to 9, wherein the composition is prepared for oral, sublingual, buccal, intranasal, intravenous, intramuscular, intraperitoneal and/or inhalation-mediated administration.

11. The composition for use according to any one of claims 1 to 10, wherein the composition is administered continuously or discontinuously.

12. The composition for use according to any one of claims 1 to 11, wherein the composition is administered intravenously, subcutaneously, orally or via inhalation.

13. The composition for use according to any one of claims 1 to 12, wherein

i. the first agent has an 1C50 for the D2 receptor at least 20 times higher than the 1C50 for the 5-HT6 receptor, and

ii. the second agent has an 1C50 for the D2 receptor at least 20 times higher than the 1C50 for the 5-HT3 receptor.

14. The composition for use according to any one of claims 1 to 12, wherein

i. the first agent has an 1C50 for the D2 receptor at least 50 times higher than the 1C50 for the 5-HT6 receptor, and

ii. the second agent has an 1C50 for the D2 receptor at least 50 times higher than the 1C50 for the 5-HT3 receptor.

15. The composition for use according to any one of claims 1 to 12, wherein

i. the first agent has an 1C50 for the D2 receptor at least 100 times higher than the 1C50 for the 5-HT6 receptor, and

ii. the second agent has an 1C50 for the D2 receptor at least 100 times higher than the 1C50 for the 5-HT3 receptor.

16. A kit comprising: (i) a first agent that has 5-HT6 receptor antagonist activity and a second agent that has 5-HT3 receptor antagonist activity; and

(ii) a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent and/or a pharmaceutically acceptable excipient,

for use in the manufacture of an anti-psychotic and/or a medicament for the treatment and/or prevention of schizophrenia; wherein

i. the first agent has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT6 receptor,

ii. the second agent has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT3 receptor, and

iii. the first and second agent may be the same or different agents.

17. An agent with 5-HT6 receptor antagonist activity for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the agent is co-administered with a second agent and the second agent has 5-HT3 receptor antagonist activity; wherein the agent with 5-HT6 receptor antagonist activity is a selective 5-HT6 receptor antagonist that has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT6 receptor.

18. The agent with 5-HT6 receptor antagonist activity for use according to claim 17, wherein the second agent has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT3 receptor.

19. An agent with 5-HT3 receptor antagonist activity for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the agent is co-administered with a second agent and the second agent has 5-HT6 receptor antagonist activity; wherein the agent with 5-HT3 receptor antagonist activity is a selective 5-HT3 receptor antagonist that has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT3 receptor.

20. The agent with 5-HT3 receptor antagonist activity for use according to claim 19, wherein the second agent has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT6 receptor.