WO2011156557A2

WO2011156557A2 - Compounds active at the neurotensin receptor

Info

Publication number: WO2011156557A2
Application number: PCT/US2011/039731
Authority: WO
Inventors: James B. Thomas; Scott P. Runyon
Original assignee: Thomas James B; Runyon Scott P
Priority date: 2010-06-11
Filing date: 2011-06-09
Publication date: 2011-12-15
Also published as: WO2011156557A3

Abstract

The present invention relates to compounds that are active at neurotensin receptors and represented by the formula:(I) where the structural variables are defined herein. The compounds can be used for a variety of therapies, including modulating dopamine transmission, treating Parkinsons disease, preventing a relapse to drug seeking, providing an antipsychotic effect, providing neuroprotection, treating pain, treating cancer, and inhibiting cancer progression.

Description

TITLE OF THE INVENTION

COMPOUNDS ACTIVE AT THE NEUROTENSIN RECEPTOR

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

The invention described herein is supported by the National Institutes of Health Grant No. 1 R01 DA024702-01. The U.S. Government may have certain rights to this invention.

CONTINUING APPLICATION INFORMATION

This application claims benefit of priority to U.S. provisional application Serial No. 61 /353,897, filed on June 1 1 , 2010, the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

The present invention relates to compounds that are active at neurotensin receptors which can be used to treat a variety of conditions.

DESCRIPTION OF THE BACKGROUND

Neurotensin (NT) is a tridecapeptide identified over thirty years ago ¹ that is widely distributed in the central and peripheral nervous systems of many mammalian species including humans and functions as both a neurotransmitter and neuromodulator^2"6. Cloning of the gene encoding this peptide revealed that it is structurally related to neuromedin N and that both are synthesized from a common precursor ⁷' ⁸.

It has been shown that NT is co-localized with mesolimbic dopamine and modulates its transmission,^9"" functionally antagonizing dopamine in the mesolimbic system while increasing dopaminergic transmission in the nigrastriatal system ¹²' '³. In fact, all major dopaminergic pathways are subject to neurotensins influence¹⁴.

Neurotensin modulates both dopaminergic and glutamatergic inputs to medium spiny neurons in the nucleus accumbens (NAcc) and thereby influences the phosphorylation of the important signal transmission molecule DARPP-32. This is hypothesized to be a critical link in the brains response to psychostimulants ' ^{5" 17}. NT has also been shown to modulate hormone secretion from the anterior pituitary gland ^{l 9}. Some of the cellular activities ascribed to this peptide include cyclic inositide production, phosphotidyl inositol turnover, intracellular calcium influx, phopholipase C and Na⁺, ⁺, -ATPase activation ^{, 9"24}.

In the brain NT exerts a host of effects some of which include hypothermia, ^25'21 motor coordination,²⁸ sedation, ²⁵ analgesia, ²⁹ hypotension, and anti-psychotic-like effects ³⁰. As a paracrine/endocrine modulator in the periphery, NT oversees a host of activities of the digestive tract and cardiovascular system and is one of several regulators of gut motility³¹. Additionally, NT has been shown to act as a growth factor on normal and cancer cells as well as playing a role in the adhesion factor of cancer cells^32"34.

Neurotensin achieves its effects through interaction with three receptor proteins as well as heterodimeric combinations of these three. The three NT binding sites that have been described to date, though there may be more,³⁵ named NTR1 , NTR2 and NTR3 (NTS 1 , NTS2, and NTS3; NTR-1 , NTR-2, NTR-3; NTRH, NTRL) have been identified, sequenced and cloned^35"42.

Both NTR1 and NTR2 are G-protein coupled receptors (GPCR) and are co-localized in the mesolimbic system. This is very important from a drug development point of view since GPCRs are an historically druggable class of protein. Indeed, most of the drugs ever developed target GPCRs. The third is mostly an intracellular binding site and is a protein identical to gp95/sortilin and possesses but a single transmembrane spanning helical region.

Recently, a splice variant of NTR2 was described, vNTR2, and has been shown to possess 5 transmembrane spanning regions and forms heteordimers with NTR2 throughout the CNS . From an anatomical perspective, NTR1 is highly localized in specific regions ³' ^4' whereas NTR2 are more widely dispersed and make up most of the NT binding sites in the brain ⁵.

Interestingly, the ventral tegmentum area (VTA) and substantia nigra are the only two brain regions where significant concentrations of each of the receptors coexist. The nucleus accumbens (NAc) that receives dopaminergic inputs from the VTA and glutamatergic inputs from the prefrontal cortex has only NTR2 receptors⁴⁵. NT-like immunoreactive fibers and cell bodies have been detected in multiple brain regions involved in nociceptive transmission and modulation including the periaqueductal grey (PAG), rostoventral medulla (RVM) and the dorsal horn of the spinal cord. Regulation of Dopamine— The ability of the neurotensin receptors to modulate DA transmission in regions of the brain critical to reward processing and learning supports the notion that compounds acting on the NT receptor system will be useful for treating maladies associated with control of dopamine including Parkinsons disease, substance abuse⁴⁶ hyperactivity⁴⁷, neuroprotection⁴⁸, antipsychotic⁴⁹, cognitive enhancers⁵⁰, anxiolytics⁴⁶ prevention of relapse to drug seeking.

Acute Pain— The demonstration that icv administrstion of the peptide neurotensin (NT) produces a strong, naloxone^nsensitive analgesic effectjn a variety of animal models indicates that acute pain may be treated with compounds interacting with NT receptors.^{5 1} Chronic pain— The observations that NT mRNA expression is increased in the brainstem⁵² in several models of chronic pain including polyarthritis⁵³, unilateral hindpaw complete Freunds' adjuvant (CFA)⁵⁴ and chronic constriction injury (CO)⁵⁵ and that the mRNA for NTR2 is upregulated in dorsal root ganglia neurons following peripheral axotomy⁵⁶ suggests that compounds interacting at NT receptors will be of value in the management of chronic pain.

Cancer— The role of NT in cancer has piqued a great deal of interest in the past few years with mounting evidence that NTR1 is over expressed in a number of human cancers.⁵⁷ Evidence also suggests that NTR3 is involved in cancer progression.^58"5 There are several tumor cells that can both secrete NT and express NT receptors and this adaptation allows tumor cells to stimulate their own growth in an autocrine manner as well as the growth of other neoplastic cells using paracrine signaling⁵⁹ Other studies have confirmed that NT promotes breast cancer progression and is involved in the cellular migration, invasion and tumor growth.⁶⁰

Very few nonpeptide ligands have been described for any NT receptor^{61 "63}. The most widely studied small-molecule compounds are the pyrazole-based SR48692 and SR142948 (1 , 2 Figure 1 ) and the H i histamine antagonist levocabastine (Livostin, 3). Barroso and Labbe-Jullie et al. describe point mutation and receptor modeling studies of interest to the development of nonpeptide ligands for NT receptor.⁶⁴'⁶⁵

All known NTR 1 receptor modeling studies demonstrated that the terminal amino acid in both the peptide agonist and small-molecule antagonist ligands is of primary importance to the ligand/receptor interaction. Both ligand types were proposed to anchor on three key residues Arg³²⁷, Met²⁰⁸ and Phe^{33 1} of the NTR1 receptor. The Arg³²⁷ residue was suggested to bind the Leu¹³ terminal residue in the peptide agonist NT and the carboxyl group in the nonpeptide antagonist 1. The side chains of the amino acids were proposed to interact with Met^/us and Phe ,33 1

SUMMARY OF THE INVENTION

It is an object of the present invention to provide compounds active at neurotensin receptors. It is another object of the invention to provide compositions containing such compounds and methods of treatment utilizing such compounds and compositions.

The objects of the present invention may be accomplished with a compound represented b formula (I):

where

each Y is, independently, H, CN, halogen, (C_rC₆)alkyl, (Ci-C₆)perfluoroalkyl, (C₃- C₈)alkenyl, (C₃-C₈)cycloalkyl, (C₃-C₈)perfluorocycloalkyl, (C₃-C₈)cycloalkylmethyl, (C₃-C8)perf!uorocycloalkylmethyl, phenyl, halogenated phenyl, benzyl, halogenated benzyl, phenyloxy, halogenated phenyloxy, (Ci-C₆)alkoxy, C(=0)R², CONR⁵R⁶, SR², SOR², S0₂R², S0₂NR⁵R⁶, NR⁵R⁶, NR⁵C=OR², NR⁵C=0NR⁵R⁶, NR⁵C0₂R², OR², or an aromatic or nonaromatic heterocyclic group;

R¹ is substituted or unsubstituted aryl or heteroaryl;.

each R² is, independently, (Ci-C₆)alkyl, (C|-C₆)perfluoroalkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)perfluorocycloalkyl, (C₃-C₈)cycloalkylmethyl, (C₃-C₈)perfluorocycloalkylmethyl, phenyl, halogenated phenyl, benzyl, or halogenated benzyl;

R³ is H, (C,-C₆)alkyl, (C,-C₆)perfluoroalkyl, (C₃-C₈)cycloalkyl,

(C₃-C₈)perfluorocycloalkyl, (C₃-C₈)cycloalkylmethyl, or (C₃-C₈)perfluorocycloalkylmethyl;

R⁴ is H, (C_rC₆)alkyl, (C,-C₆)perfluoroalkyl, (C₃-C₈)cycloalkyl,

(C₃-C₈)perfluorocycloalkyl, (C₃-C₈)cycloalkylmethyl, or (C₃-C₈)perfluorocycloalkylmethyl; or R' and R may be joined to form a 5- 10 membered carbocyclic ring, bridged carbocyclic ring, or fused carbocyclic ring.

R⁵ is H, (C,-C₆)alkyl, (C,-C₆)perfiuoroalkyl, (C₃-C₈)cycloalkyl,

(C₃-C₈)perfluorocycloalkyl, (C₃-C₈)cycloalkylmethyl, or (C₃-C8)perfluorocycloalkylmethyl;

R⁶ is H, (C_rC₆)alkyl, (C,-C₆)perfluoroalkyl, or (C₃-C₈)cycloalkyl,

(C₃-C₈)perfluorocycloalkyl, (C₃-C₈)cycloalkylmethyl, (C₃-C₈)perfluorocycloalkylmethyl; or R⁵ and R⁶ may be joined to form a 5-7 membered nonaromatic heterocyclic group, or a pharmaceutically acceptable salt thereof.

The present invention also includes a method of modulating dopamine transmission, comprising administering an effective amount of the compound described above to a subject in need thereof.

The present invention also includes a method of treating Parkinsons disease, substance abuse or hyperactivity, comprising administering an effective amount of the compound described above to a subject in need thereof.

The present invention also includes a method of prevention a relapse to drug seeking, comprising administering an effective amount of the compound described above to a subject in need thereof.

The present invention also includes a method of providing an antipsychotic effect, comprising administering an effective amount of the compound described above to a subject in need thereof.

The present invention also includes a method of providing neuroprotection, comprising administering an effective amount of the compound described above to a subject in need thereof.

The present invention also includes a method of treating pain, comprising

administering an effective amount of the compound described above to a subject in need thereof.

The present invention also includes method of treating cancer, comprising

The present invention also provides a method of inhibiting cancer progression, comprising administering an effective amount of the compound described above to a subject in need thereof. A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following Figures in conjunction with the detailed description below.

BRIEF DESCRIPTION OF THE FIGURE

Figure 1 : Chemical structures of compounds represented by formula 1 , 2, 3, 4, and 5.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of the present invention, referring to formula (I) discussed above, it is preferable that at most four of the Y groups are other than H as defined above. More preferably, at most three of the Y groups are other than H as defined above. More preferably, one or two of the Y groups are other than hydrogen.

In another embodiment of the present invention, the compounds are represented by the formula:

In a preferred embodiment, Y is other than hydrogen as defined above. In another embodiment, the compounds of the present invention are represented by the formula:

In a preferred embodiment, each R² is, independently, (Ci-C₆)alkyl.

In another embodiment, each Y in the compounds of the present invention is H. Such compounds are re resented by the formula:

In one embodiment of the invention, each Y is, independently, H, CN, halogen, (C,-C₆)alkyl, (Ci-C₆)perfluoroalkyl, (C₃-C₈)alkenyl, (C₃-C₈)cycloalkyl, (C₃- C8)perfluorocycloalkyl, (C₃-C₈)cycloalkylmethyl, (C₃-C )perfluorocycloalkylmethyl, phenyl, halogenated phenyl, benzyl, halogenated benzyl, (Ci-C₆)alkoxy, C(=0)R², CONR⁵R⁶, SR², SOR², S0₂R², S0₂NR⁵R⁶, NR⁵R⁶, NR⁵C=OR², NR⁵C=ONR⁵R⁶, NR⁵C0₂R², OR², pyrrolidine, piperidine, mo holine, piperazine, N-alkylpiperazine, N-acylpiperazine, pyridine, pyrimidine, pyrazole, imidazole, triazine, or thiazole.

In another embodiment of the invention, each Y is, independently, H, halogen, or (Ci-C₆)alkoxy.

In another embodiment of the invention, each Y is, independently, H, chloro, trifluoromethoxy, or methoxy.

In one embodiment, R¹ is substituted or unsubstituted aryl or heteroaryl. In another embodiment of he invention, R¹ is

In another embodiment of the invention,

R³ represents H, (C C₆)alkyl, (Ci-C₆)perfluoroalkyl, (C₃-C₈)cycloalkyl, (C₃- C₈)perfluorocycloalkyl;

R⁴ represents H, (Ci-C₆)alkyl, (C|-C₆)perfluoroalkyl, (C₃-C₈)cycloalkyl, or (C₃- Csiperfluorocycloalkyl,

or R³ and R⁴ may be joined to form a 5 - 10 membered carbocyclic ring, bridged carbocyclic ring or fused bicyclic ring. In another embodiment of the invention, one of R³ and R⁴ are other than H as defined above.

In another embodiment of the invention,

R³ represents H, (C_rC₆)alkyl, (C_rC₆)perfluoroalkyl, (C₃-C₈)cycloalkyl;

R⁴ represents H, (Ci-C₆)alkyl, (Ci-C₆)perfluoroalkyl, or (C₃-C₈)cycloalkyl, or R³ and R⁴ may be joined to form a 5-10 membered carbocyclic ring, bridged carbocyclic ring, or fused bicyclic ring.

In another embodiment of the invention,

R³ represents H, (C ,-C₆)alkyl, (C₃-C₈)cycloalkyl;

R⁴ represents H, (C_rC₆)alkyl, (C₃-C₈)cycloalkyl,

or R³ and R⁴ may be joined to form a 5-10 membered carbocyclic ring, bridged carbocyclic ring, or fused bicyclic ring.

In another embodiment of the invention, R³ is (Ci-C₆)alkyl and R⁴ is H.

In another embodiment of the invention, R³ and R⁴ are joined to form a 5- 10 membered carbocyclic ring, bridged carbocyclic ring, or fused carbocyclic ring

In another embodiment of the invention,

R⁵ represents H, (Ci-C₆)alkyl;

R⁶ represents H, (C_rC₆)alkyl,

or R⁵ and R⁶ may be joined to form a pyrrolidine, piperidine, morpholine, piperazine, N-alkylpiperazine, N-acylpiperazine.

In another embodiment of the invention, R⁵ and R⁶ may be joined to form a pyrrolidine, piperidine, morpholine, piperazine, N-alkylpiperazine, or N-acylpiperazine group.

In another embodiment of the invention,

each Y is, independently, H, methoxy, or trifiuoromethoxy;

R¹ is

R² is (C,-C₆)alkyl;

R³ independently represents H, isobutyl, n-butyl, or cyclohexyl; R⁴ independently represents H, isobutyl, n-butyl or cyclohexyl,

or R³ and R⁴ may be joined to form a 5-10 membered carbocyclic

In another embodiment of the invention,

each Y is, independently, halogen or (Ci-C₆)alkoxy;

R¹ is

R² is (C,-C₆)alkyl;

R³ is (C,-C₆)alkyl; and

R⁴ is H.

In another embodiment of the invention, the compound is represented by the formula

In another embodiment of the invention, the compound is represented by the formula:

The compounds of the present invention may be in the form of a pharmaceutically acceptable salt via protonation with a suitable acid. The acid may be an inorganic acid or an organic acid. Suitable acids include, for example, hydrochloric, hydroiodic, hydrobromic, sulfuric, phosphoric, citric, acetic, fumaric, tartaric, and formic acids.

The compounds of the present invention are active at the neurotensin receptor. As such, the compounds of the present invention may be used to modulate dopamine

transmission.

The compounds of the present invention may also be used to treat Parkinsons disease, substance abuse or hyperactivity.

The compounds of the present invention may also be used to prevent a relapse to drug seeking.

The compounds of the present invention may be used to provide an antipsychotic effect.

The compounds of the present invention may be used to provide neuroprotection.

The compounds of the present invention may be used to treat pain. In one

embodiment, the pain is acute pain or chronic pain.

The compounds of the present invention may be used to treat cancer. Particular types of cancer include cancer of the prostate, lung, thyroid, pancreas, colon, rectum, pituitary, breast and any cancer in which down regulation or suppression of neurotensin receptors inhibits the migration of cancer cells and/or suppresses their ability to invade normal tissues.

The compounds of the present invention may be used to inhibit cancer progression.

The compounds may be administered in an effective amount by any of the conventional techniques well-established in the medical field. For example, the compounds may be administered orally, intraveneously, or intramuscularly. When so administered, the inventive compounds may be combined with any of the well-known pharmaceutical carriers and additives that are customarily used in such pharmaceutical compositions. For a discussion of dosing forms, carriers, additives, pharmacodynamics, etc., see Kirk-Othmer Encyclopedia of Chemical Technology, Fourth Edition, Vol. 18, 1996, pp. 480-590, incorporated herein by reference. The patient is preferably a mammal, with human patients especially preferred. Effective amounts are readily determined by those of ordinary skill in the art.

The compounds of the present invention can be administered as a single dosage per day, or as multiple dosages per day. When administered as multiple dosages, the dosages can be equal doses or doses of varying amount, based upon the time between the doses (i.e. when there will be a longer time between doses, such as overnight while sleeping, the dose administered will be higher to allow the compound to be present in the bloodstream of the patient for the longer period of time at effective levels). Preferably, the compound and compositions containing the compound are administered as a single dose or from 2-4 equal doses per day.

Suitable compositions containing the present compounds further comprise a physiologically acceptable carrier, such as water or conventional pharmaceutical solid carriers, and if desired, one or more buffers and other excipients.

Halogen substituents may be fluorine, chlorine, bromine or iodine. Chlorine is particularly preferred.

The ranges given for groups discussed above include all specific values and subranges therebetween. For example, a (C1 -C6) alkyl group includes alkyl groups having 1 , 2, 3, 4, 5 or 6 carbon atoms, and all subranges therebetween.

Unless stated otherwise, the groups discussed above may be linear, branched or cyclic unless noted otherwise.

The present invention includes any and all combination of the different structural groups defined above, including those combinations not specifically set forth above.

As used throughout this disclosure, the terms "alkyl group" encompass all structural isomers thereof, such as linear, branched and cyclic alkyl groups and moieties, unless noted otherwise. Unless stated otherwise, all alkyl groups described herein may have 1 to 8 carbon atoms, inclusive of all specific values and subranges therebetween, such as 2, 3, 4, 5, 6, or 7 carbon atoms. Representative examples include methyl, ethyl, propyl, butyl and cyclohexyl. The term "cycloalkyl" refers to cyclic alkyl groups only, such as cycloproyl, cyclopentyl and cyclohexyl. In fact, all of the carbon atom ranges for all groups and substituents includes all specific values and subranges therebetween.

Perfluoroalkyl groups are preferred substituents in embodiments of the present invention. Examples of perfluoroalkyl groups include trifluoromethyl (-CF₃) and

peri uoroethyl (-CF₂CF₃).

An alkenyl group as referred to herein has one or more double bonds. As will be readily appreciated, when an alkenyl group is bonded to a heteroatom a double bond is not formed with the carbon atom bonded directly to the heteroatom. Unless stated otherwise, all carbon atoms ranges for alkenyl groups include all specific values and subranges

therebetween, such as 3, 4, 5, 6, or 7 carbon atoms. A representative alkenyl group is - CH₂CH=CH₂.

Aromatic and nonaromatic heterocyclic groups may generally contain 3 to 8 ring members and have at least one heteroatom. The heteroatom may be N, O or S. Examples of suitable groups include piperidine, morpholine, piperazine, N-alkylpiperazine, N- acylpiperazine, pyridine, pyrimide, pyrazole, imidazole, triazine, thiazole, pyrrolidine, piperidine, morpholine, piperazine, N-alkylpiperazine, and N-acylpiperazine.

The compounds of the present invention may be in the form of a pharmaceutically acceptable salt via protonation of the amines with a suitable acid. The acid may be an inorganic acid or an organic acid. Suitable acids include, for example, hydrochloric, hydroiodic, hydrobromic, sulfuric, phosphoric, citric, acetic, fumaric, tartaric, and formic acids.

The synthesis of the tetrazole compounds described herein is illustrated in the following Scheme. A convergent approach is utilized wherein two key components, illustrated herein by pyrazole carboxylic acid F and tetrazole amine K, are condensed in a key step under the action of a suitable coupling reagent (illustrated here by 2-( l H-benzotriazol- l - yl)- l , l ,3,3-tetramethyluronium hexafluorophosphate, HBTU). The required pyrazole carboxylic acids, represented here by F, can be prepared according to the method described by Labeeuw⁶². Briefly, condensation of a suitable acetophenone derivative, such as A, with ethyl oxalate (B) under the action sodium methoxide in methanol provides a beta-ketoester (C). Condensation of C with a suitable hydrazine derivative, such as D, in refluxing acetic acid gives an intermediate ester E. Hydrolysis of E can be accomplished in many ways. The method illustrated herein involves treatment with lithium hydroxide in 1 ,4-dioxane followed by protonation using HC1 to give a pyrazole carboxylic acid such as F.

The required tetrazole amines can be prepared according to the method of

Sureshbabu⁶⁶ wherein a given fluorenylmethyloxycarbonyl (Fmoc) protected amino acid, illustrated here for Fmoc-leucine (G), is converted first to a carboxamide such as H using di- r/-butyl dicarbonate and pyridine. This intermediate is then dehydrated using triflic anhydride and pyridine to give a nitrile intermediate, such as I, suitable for conversion to a tetrazole, such as J, under the action of sodium azide and zinc bromide. Removal of the Fmoc group using diethyamine provides the tetrazole amine K in a form that is suitable for coupling to F in the key step to provide the desired target compounds such as L.

The compounds of the present invention are particularly useful for treating addiction, such as addiction to ***e, alcohol, methamphetamine, nicotine, heroin, and other drugs of abuse. With respect to nicotine, the compounds of the present invention are also useful in treating nicotine withdrawal effects.

The compounds may be administered in an effective amount by any of the

conventional techniques well-established in the medical field. For example, the compounds may be administered orally, intraveneously, or intramuscularly. When so administered, the inventive compounds may be combined with any of the well-known pharmaceutical carriers and additives that are customarily used in such pharmaceutical compositions. For a discussion of dosing forms, carriers, additives, pharmacodynamics, etc., see Kirk-Othmer Encyclopedia of Chemical Technology, Fourth Edition, Vol. 18, 1996, pp. 480-590, incorporated herein by reference. The patient is preferably a mammal, with human patients especially preferred. Effective amounts are readily determined by those of ordinary skill in the art.

The compounds of the invention may be synthesized by, for example, the schemes shown in the following Examples. Those skilled in the art will appreciate that the synthesis of the exemplified compounds can readily be adapted for the preparation of other compounds within the scope of formula I. EXAMPLES

Having generally described this invention, a further understanding can be obtained by reference to certain specific examples which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified.

Example 1

Compounds 1 , 4 and 5 were tested as described below.

Table 1. Pyrazole Agonists and Antagonists in NTRl and NTR2 FLIPR and β-Arrestin Assays

This compound is a potent agonist of calcium signaling in the NTR2 FLIPR assay but its EC50 has not been determined.

In fact, replacement of the adamantyl amino acid in 1 with L-leucine changed the intrinsic activity from antagonists (K_c = 36 nM) to that of a potent partial agonist 4 (EC₅₀ = 67 nM, Em_ax of 51 %). This clearly demonstrated that the amino acid in these compounds exerts a powerful directing effect on the compounds intrinsic behavior and can confer either agonist or antagonist activity depending on its substructure. The NTRl specificity of the observed calcium release for 4 was demonstrated by blocking with the NTRl antagonist (1) as described earlier (data not shown). The tetrazole variant (5) of compound 4 was tested to determine if it too would possess agonist activity. In our hands, compound 5 (E s = 40 nM, E_max of 50%) was equally active with compound 4 indicating that there is sufficient room in the receptor to accommodate the much larger volume requirement demanded by the tetrazole in 5 relative to the carboxylic acid in 4. Since these are the first known small-molecule agonists for this receptor, compound 4 was tested in rats to determine their ADME properties. As shown in Table 2, both compounds 4 and 5 are readily absorbed, but compound 5 has much greater plasma stability.

Table 2. Absorption and Stability Data for Compounds 4 and 5 in Rat

Plasma

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

REFERENCES

1. Caraway, R.; Leeman, S. E. J. Biol. Chem 1973, 248, 6854-6861 .

2. Perron, A.; Sarret, P.; Gendron, L.; Stroh, T.; Beaudet, A. J Biol Chem 2005, 280, (1 1 ), 10219-27.

3. Quirion, R.; Rowe, W. B.; Lapchak, P. A.; Araujo, D. M.; Beaudet, A. Ann N Y Acad Sci 1992, 668, 109-19.

4. Sarret, P.; Perron, A.; Stroh, T.; Beaudet, A. J Comp Neurol 2003, 461 , (4), 520-38.

5. Uhl, G. R. Ann N Y Acad Sci 1982, 400, 132-49.

6. Walker, N.; Lepee-Lorgeoux, I.; Fournier, J.; Betancur, C; Rostene, W.; Ferrara, P.;

Caput, D. Brain Res Mol Brain Res 1998, 57, (2), 193-200.

7. Dobner, P. R.; Barber, D. L.; Villa-Komaroff, L.; McKiernan, C. Proc Natl Acad Sci U S A 1987, 84, (10), 3516-20. 9731

8. Minamino, N.; Kangawa, K.; Matsuo, H. Biochem Biophys Res Commun 1984, 122, (2), 542-9.

9. Hokfelt, T.; Everitt, B. J.; Theodorsson-Norheim, E.; Goldstein, M. J Comp Neurol 1984, 222, (4), 543-59.

10. Kalivas, P. W.; Miller, J. S. Brain Res 1984, 300, (1), 157-60.

1 1 . Kalivas, P. W.; Nemeroff, C. B.; Prange, A. J., Jr. Eur J Pharmacol 1982, 78, (4), 471 -4.

12. Ford, A. P.; Marsden, C. A. Brain Res 1990, 534, (1-2), 243-50.

13. Nemeroff, C. B.; Hernandez, D. E.; Luttinger, D.; Kalivas, P. W.; Prange, A. J., Jr.

Ann N Y Acad Sci 1982, 400, 330-44.

14. Drumheller, A. D.; Gagne, M. A.; St-Pierre, S.; Jolicoeur, F. B. Neuropeptides 1990, 15, (3), 169-78.

15. Lee, K.; Kim, Y.; Kim, A. M.; Helmin, K.; Nairn, A. C; Greengard, P. Proc Natl Acad Sci USA 2006, 103, (9), 3399-3404.

16. Matsuyama, S.; Fukui, R.; Higashi, H.; Nishi, A. Eur J Neurosci 2003, 18, (5), 1247- 53.

17. Matsuyama, S.; Higashi, H.; Maeda, H.; Greengard, P.; Nishi, A. J Neurochem 2002, 81 , (2), 325-34.

18. Smith, M. J.; Jennes, L. Reproduction 2001 , 122, (1 ), 1 -10.

19. Memo, M.; Castelletti, L.; Missale, C; Valerio, A.; Carruba, M.; Spano, P. F. J

Neurochem 1986, 47, (6), 1689-95.

20. Bozou, J. C; Amar, S.; Vincent, J. P.; Kitabgi, P. Mol Pharmacol 1986, 29, (5), 489- 96.

21. Gilbert, J. A.; Richelson, E. Eur J Pharmacol 1984, 99, (2-3), 245-6.

22. Hermans, E.; Maloteaux, J. M.; Octave, J. N. Brain Res Mol Brain Res 1992, 15, (3- 4), 332-8.

23. Lopez Ordieres, M. G.; Rodriguez de Lores Arnaiz, G. Peptides 2000, 21 , (4), 571 -6.

24. Snider, R. M.; Forray, C; Pfenning, M.; Richelson, E. J Neurochem 1986, 47, (4), 1214-8.

25. Nemeroff, C. B.; Bissette, G.; Prange, A. J., Jr.; Loosen, P. T.; Barlow, T. S.; Lipton, M. A. Brain Res 1977, 128, (3), 485-96.

26. Bissette, G.; Nemeroff, C. B.; Loosen, P. T.; Prange, A. J., Jr.; Lipton, M. A. Nature 1976, 262, (5569), 607-9. Bissette, G.; Luttinger, D.; Mason, G. A.; Hernandez, D. E.; Loosen, P. T. Ann N Y Acad Sci 1982, 400, 268-82.

Pettibone, D. J.; Hess, J. F.; Hey, P. J.; Jacobson, M. A.; Leviten, M.; Lis, E. V.; Mallorga, P. J.; Pascarella, D. M.; Snyder, M. A.; Williams, J. B.; Zeng, Z. J

Pharmacol Exp Ther 2002 , 300, ( 1 ), 305 - 13.

Clineschmidt, B. V.; Martin, E. E.; Veber, D. F. Ann N Y Acad Sci 1982, 400, 283- 306.

Kinkead, B.; Nemeroff, C. B. Int Rev Neurobiol 2004, 59, 327-49.

Laburthe, M.; Couvineau, A.; Amiranoff, B.; Voisin, T. Baillieres Clin Endocrinol Metab 1994, 8, ( 1 ), 77- 1 10.

Amorino, G. P.; Parsons, S. J. Crit Rev Eukaryot Gene Expr 2004, 14, (4), 287-300. Maoret, J. J.; Anini, Y.; Rouyer-Fessard, C; Gully, D.; Laburthe, M. Int J Cancer 1999, 80, (3), 448-54.

Sethi, T.; Langdon, S.; Smyth, J.; Rozengurt, E. Cancer Res 1992, 52, (9 Suppl), 2737s-2742s.

Vincent, J. P.; Mazella, J.; itabgi, P. Trends Pharmacol Sci 1999, 20, (7), 302-9. Vita, N.; Oury-Donat, F.; Chalon, P.; Guillemot, M.; Kaghad, M.; Bachy, A.;

Thurneyssen, O.; Garcia, S.; Poinot-Chazel, C; Casellas, P.; Keane, P.; Le Fur, G.; Maffrand, J. P.; Soubrie, P.; Caput, D.; Ferrara, P. Eur J Pharmacol 1998, 360, (2-3), 265-72.

Vita, N.; Laurent, P.; Lefort, S.; Chalon, P.; Dumont, X.; Kaghad, M.; Gully, D.; Le Fur, G.; Ferrara, P.; Caput, D. FEBS Lett 1993, 317, (1 -2), 139-42.

Tanaka, K.; Masu, M.; Nakanishi, S. Neuron 1990, 4, 847-854.

Mazella, J.; Zsurger, N.; Navarro, V.; Chabry, J.; Kaghad, M.; Caput, D.; Ferrara, P.; Vita, N.; Gully, D.; Maffrand, J. P.; Vincent, J. P. J Biol Chem 1998, 273, (41 ),

26273-6.

Mazella, J.; Botto, J.; Guillemare, E.; Coppola, T.; Sarret, P.; Vincent, J. P. Journal of Neuroscience 1996, 16, (18), 5613-5620.

Chalon, P.; Vita, N.; Kaghad, M.; Guillemot, M.; Bonnin, J.; Delpech, B.; Le Fur, G.; Ferrara, P.; Caput, D. FEBS Lett 1996, 386, (2-3), 91 -4.

Martin, S.; Navarro, V.; Vincent, J. P.; Mazella, J. Gastroenterology 2002, 123, (4), 1 135-43. 43. Elde, R.; Schalling, M.; Ceccatelli, S.; Nakanishi, S.; Hokfelt, T. Neurosci Lett 1990, 120, (1 ), 134-8.

44. Nicot, A.; Rostene, W.; Berod, A. J Comp Neurol 1994, 341 , (3), 407- 19.

45. Walker, N.; Lepee-Lorgeoux, I.; Foumier, M.; Betancur, C; Rostene, W.; Ferrara, P.;

Caput, D. Molecular Brain Research 1998, 57, 193-200.

46. Torregrossa, M. M; Kalivas, P. W. J Pharmacol Exp Ther 2008, 325, (2), 556-66.

47 Feifel, D.; Melendez, G.; Murray, R. J.; Tina Tran, D. N.; Rullan, M. A.; Shilling, P.

D. Psychopharmacology (Be ) 2008, 200, (2), 197-203.

48 Torup, L.; Borsdal, J.; Sager, T. Neurosci Lett 2003, 351 , (3), 173-6.

49. Feifel, D.; Reza, T. L.; Wustrow, D. J.; Davis, M. D. J Pharmacol Exp Ther 1999,

288, (2), 710-3.

50. Grimond-Billa, S. K.; Norman, C; G, W. B.; Cassaday, H. J. J Psychopharmacol

2008, 22, (3), 290-9.

51. Clineschmidt, B. V.; Martin, E. E.; Veber, D. F. Ann N Y Acad Sci 1982, 400, 283- 306.

52. Williams, F. G.; Beitz, A. J. Brain Res 1993, 61 1 , (1 ), 87-102.

53. Colpaert, F. C. Pain 1987, 28, (2), 201 -22.

54. Stein, C; Millan, M. j.; Herz, A. Pharmacol Biochem Behav 1988, 31 , (2), 455-51.

55. Bennett, G. J.; Xie, Y. . Pain 1988, 33, ( 1), 87- 107.

56. Xiao, H. S.; Huang, Q. H.; Zhang, F. X.; Bao, L.; Lu, Y. J.; Guo, C; Yang, L.; Huang, W. J.; Fu, G.; Xu, S. H.; Cheng, X. P.; Yan, Q.; Zhu, Z. D.; Zhang, X.; Chen, Z.; Han, Z. G.; Zhang, X. Proc Natl Acad Sci U S A 2002, 99, (12), 8360-5.

57. Carraway, R. E.; Plona, A. M. Peptides 2006, 27, (10), 2445-60.

58. Schaeffer, P.; Laplace, M. C; Bernat, A.; Prabonnaud, V.; Gully, D.; Lespy, L.;

Herbert, J. M. J Cardiovasc Pharmacol 1998, 31 , (4), 545-50.

59. Heasley, L. E. Oncogene 2001, 20, (13), 1563-9.

60. Souaze, F.; Dupouy, S.; Viardot-Foucault, V.; Bruyneel, E.; Attoub, S.; Gespach, C;

Gompel, A.; Forgez, P. Cancer Res 2006, 66, (12), 6243-9.

61. Pang, Y.; Cusack, B.; Groshan, K.; Richelson, E. J. Biol. Chem 1996, 271 , (25),

15060-15068.

62. Labeeuw, B.; Gully, D.; Jeanjean, F.; Molimard, J.-C; Boigegrain, R. 1 - Phenylpyrazole-3-carboxamides acting on neurotensin receptors. 1996. 63. Gully, D.; Canton, M.; Boigegrain, R.; Jeanjean, F.; Molimard, J. C; Poncelet, M.; Gueudet, C; Heaulme, M.; Leyris, R.; Brouard, A.; et al. Proc Natl Acad Sci U S A 1993, 90, (1 ), 65-9.

64. Barroso, S.; Richard, F.; Nicolas-Etheve, D.; Reversat, J. L.; Bernassau, J. M.;

Kitabgi, P.; Labbe-Jullie, C. J Biol Chem 2000, 275, (1 ), 328-36.

65. Labbe-Jullie, C; Barroso, S.; Nicolas-Eteve, D.; Reversat, J. L.; Botto, J. M.; Mazella, J.; Bernassau, J. M.; Kitabgi, P. J Biol Chem 1998, 273, (26), 16351 -7.

66. Sureshbabu, V.; Venkataramanarao, R.; Naik, S.; Chennakrishnareddy, G.

Tetrahedron Letters 2007, 48, 7038-7041.

Claims

1. A compound re resented by formula (I):

wherein

each Y is, independently, H, CN, halogen, (Ci-C₆)alkyl, (Ci-C₆)perfluoroalkyl, (C₃- C8)alkenyl, (C₃-C8)cycloalkyl, (C₃-C8)perfluorocycloalkyl, (C₃-C8)cycloalkylmethyl, (C₃-C8)perfluorocycloalkylmethyl, phenyl, halogenated phenyl, benzyl, halogenated benzyl, phenyloxy, halogenated phenyloxy, (C,-C₆)alkoxy, C(=0)R², CONR⁵R⁶, SR², SOR², S0₂R², S0₂NR⁵R⁶, NR⁵R⁶, NR⁵C=OR², NR⁵C=ONR⁵R⁶, NR⁵C0₂R², OR², or an aromatic or nonaromatic heterocyclic group;

R¹ is substituted or unsubstituted aryl or heteroaryl;

each R² is, independently, (Ci-C₆)alkyl, (Ci-C₆)perfluoroalkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)perfluorocycloalkyl, (C₃-C₈)cycloalkylmethyl, (C₃-C₈)perfluorocycloalkylmethyl, phenyl, halogenated phenyl, benzyl, or halogenated benzyl;

R³ is H, (C_rC₆)alkyl, (C,-C₆)perfluoroalkyl, (C₃-C₈)cycloalkyl,

(C₃-C₃)perfluorocycloalkyl, (C₃-C₈)cycloalkylmethyl, or (C₃-C8)perfiuorocycloalkylmethyl;

R⁴ is H, (C,-C₆)alkyl, (C,-C₆)perfluoroalkyi, (C₃-C_x)cycloalkyl,

(C₃-C₈)perfluorocycloalkyl, (C3-C₈)cycloalkylmethyl, or (C₃-C8)perfiuorocycloalkylmethyl; or R³ and R⁴ may be joined to form a 5-10 membered carbocyclic ring, bridged carbocyclic ring, or fused carbocyclic ring;

R⁵ is H, (C,-C₆)alkyl, (Ci-C₆)perfluoroalkyl, (C₃-C₈)cycloalkyl,

(C₃-C₈)perfluorocycloalkyl, (C₃-C8)cycloalkylmethyl, or (C₃-C₈)perfluorocycloalkylmethyl; and R⁶ is H, (C,-C₆)alkyl, (C_rC₆)perfluoroalkyl, or (C₃-C₈)cycloalkyl,

2. The com ound of Claim 1 , which is represented by the formula:

3. The compound of Claim 1 , which is represented by the formula:

wherein Y is CN, halogen, (C C₆)alkyl, (CrC₆)perfiuoroalkyl, (C₃-C₈)alkenyl, (C₃-C₈)cycloalkyl, (C₃-C₈)perfluorocycloalkyl, (C₃-C₈)cycloalkylmethyl,

(C₃-C₈)perfluorocycloalkylmethyl, phenyl, halogenated phenyl, benzyl, halogenated benzyl, phenyloxy, halogenated phenyloxy, (C,-C₆)alkoxy, C(=0)R², CONR⁵R⁶, SR², SOR², S0₂R², S0₂NR⁵R⁶, NR⁵R⁶, NR⁵C=OR², NR⁵C=ONR⁵R⁶, NR⁵C0₂R², OR², or an aromatic or nonaromatic heterocyclic group.

4. The compound of Claim 1 , which is represented by the formula:

5. The compound of Claim 1 , which is represented by the formula:

6. The compound of Claim 1 , wherein R¹ is

7. The compound of Claim 1 , wherein each Y is, independently, H, CN, halogen, (C,-C₆)alkyl, (C,-C₆)perfluoroalkyl, (C₃-C₈)alkenyl, (C₃-C₈)cycloalkyl, (C₃- C₈)perfiuorocycloalkyl, (C₃-C₈)cycloalkylmethyl, (C3-C₈)perfluorocycloalkylmethyl, phenyl, aiogenaied phenyl, benzyl, halogenaied benzyl, (C C₆)alkoxy, C(=0)R², CONR⁵R⁶, SR², SOR², S0₂R², S0₂NR⁵R⁶, NR⁵R⁶, NR⁵C=OR², NR⁵C=ONR⁵R⁶, NR⁵C0₂R², pyrrolidine, piperidine, morpholine, piperazine, N-alkylpiperazine, N-acylpiperazine, pyridine, pyrimidine, pyrazole, imidazole, triazine, or thiazole.

8. The compound of Claim 1 , wherein each Y is, independently, H, halogen, or (C_rC₆)alkoxy.

9. The compound of Claim 1 , wherein each Y is, independently, H, chloro, trifiuoromethoxy, or methoxy.

10. The compound of Claim 1 , wherein R¹ is

The compound of Claim 1 , wherein R¹

12. The compound of Claim 1 , wherein

R³ represents H, (C_rC₆)alkyl, (C,-C₆)perfluoroalkyl, (C₃-C₈)cycloalkyl, (C₃- C₈)perfluorocycloalkyl; and

R⁴ represents H, (Ci-C₆)alkyl, (Ci-C₆)perfluoroalkyl, (C₃-C₈)cycloalkyl, or (C₃-

C₈)perfluorocycloalkyl,

or R³ and R⁴ may be joined to form a 5- 10 membered carbocyclic ring, bridged carbocyclic ring or fused bicyclic ring.

13. The compound of Claim 1 , wherein one of R³ and R⁴ are other than H as defined above.

14. The compound of Claim 1 , wherein

R³ represents H, (Ci-C₆)alkyl, (Ci-C₆)perfluoroalkyl, (C₃-C₃)cycloalkyl; and R⁴ represents H, (Ci-C₆)alkyl, (Ci-C₆)perfluoroalkyl, or (C₃-C₈)cycloalkyl, or R³ and R may be joined to form a 5-10 membered carbocyclic ring, bridged carbocyclic ring, or fused bicyclic ring.

15. The compound of Claim 1 , wherein

R³ represents H, (C,-C₆)alkyl, (C₃-C₈)cycloalkyl; and

R⁴ represents H, (C,-C₆)alkyl, (C₃-C₈)cycloalkyl,

16. The compound of Claim 1 , wherein R³ is (Ci-C₆)alkyl and R⁴ is H.

17. The compound of Claim 1 , wherein R³ and R⁴ are joined to form a 5-10 membered carbocyclic ring, bridged carbocyclic ring or fused carbocyclic ring.

18. The compound of Claim 1 , wherein

R⁵ represents H, (d-C₆)aIkyI; and

R⁶ represents H, (C_rC₆)alkyl,

or R⁵ and R⁶ may be joined to form a pyrrolidine, piperidine, morpholine, piperazine,

N-alkylpiperazine, or N-acylpiperazine.

19. The compound of Claim 1 , wherein R⁵ and R⁶ may be joined to form a pyrrolidine, piperidine, morpholine, piperazine, N-alkylpiperazine or N-acylpiperazine group.

20. The compound of Claim 1 , wherein

each Y is, independently, H, methoxy, or trifluoromethoxy;

R¹ is

R² is (C,-C₆)alkyl;

R³ independently represents H, isobutyl, n-butyl, or cyclohexyl; and

R⁴ independently represents H, isobutyl, n-butyl or cyclohexyl,

or R³ and R⁴ may be joined to form a 5 - 10 membered carbocyclic ring.

21. The compound of Claim 1 , wherein

each Y is, independently, halogen or (Ci-C₆)alkoxy;

R¹ is

R² is (C,-C₆)alkyl;

R³ is (C,-C₆)alkyl; and

R⁴ is H.

22. The compound of Claim 1 , which is represented by one the following formulae:

The compound of Claim 1 , which is represented by the formul

24. A method of modulating dopamine transmission, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.

25. A method of treating Parkinsons disease, substance abuse or hyperactivity, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.

26. A method of prevention a relapse to drug seeking, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.

27. A method of providing an antipsychotic effect, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.

28. A method of providing neuroprotection, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.

29. A method of treating pain, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.

30. The method of Claim 29, wherein the pain is acute pain or chronic pain.

31. A method of treating cancer, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.

32. A method of inhibiting cancer progression, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.

33. A method of treating cancer of the prostate, lung, thyroid, pancreas, colon, rectum, pituitary and/or breast, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.

34. A method of treating cancer in which down regulation or suppression of neurotensin receptors inhibits the migration of cancer cells and/or suppresses their ability to invade normal tissues, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.