WO2006079999A2 - Induction d'un nouvel etat psychique a l'aide d'un agoniste de 5-ht2a et d'un antagoniste de nmda - Google Patents

Induction d'un nouvel etat psychique a l'aide d'un agoniste de 5-ht2a et d'un antagoniste de nmda Download PDF

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Publication number
WO2006079999A2
WO2006079999A2 PCT/IB2006/051080 IB2006051080W WO2006079999A2 WO 2006079999 A2 WO2006079999 A2 WO 2006079999A2 IB 2006051080 W IB2006051080 W IB 2006051080W WO 2006079999 A2 WO2006079999 A2 WO 2006079999A2
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Prior art keywords
human
ht2a
nmda
nmda antagonist
receptors
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PCT/IB2006/051080
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English (en)
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WO2006079999A3 (fr
Inventor
Frederik H. Barth
Original Assignee
Barth Frederik H
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Publication date
Application filed by Barth Frederik H filed Critical Barth Frederik H
Priority to PCT/IB2006/051080 priority Critical patent/WO2006079999A2/fr
Publication of WO2006079999A2 publication Critical patent/WO2006079999A2/fr
Publication of WO2006079999A3 publication Critical patent/WO2006079999A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • a 5-HT2A agonist is any substance which exerts agonistic activity at the 5-HT2A receptor, but it may also have additional pharmacological activity.
  • a NMDA antagonist is any substance which inhibits the agonistic activity of the excitatory amino acid derivative NMDA at its receptor, but it may also have additional pharmacological activity.
  • NMDA antagonists and 5-HT2A agonists are psychosis-inducing drugs in human beings, see for example Pharmacopsychiatry 38(6):301-ll, 2005 (PMID: 16342002). These psychosis-inducing effects limit the usefulness of NMDA antagonists as drugs for the treatment of human beings, where they are being explored as neuroprotective treatments and for other therapeutic applications.
  • Ketamine is a clinically employed NMDA antagonist used for its sedative, anesthetic and analgesic properties. It is usually administered together with other drugs, such as benzo- diazepines, to reduce its psychotomimetic side effects.
  • This novel state of the human mind is characterized by mental clarity, elevated consciousness and absence of hallucinations.
  • Intelligence and creativity of a human being in which this novel state of mind is induced appear to be enhanced.
  • a neuropharmacological explanation for this phenomenon may be found in the effect a 5-HT2A agonist has on NMDA receptor mediated functions.
  • Data disclosed by Arvanov et al. in Eur J Neurosci. 1999 Aug;ll(8):2917-34, 1999 (PMID: 10457188) and Eur J Neurosci. ll(9):3064-72, 1999 (PMID: 10510170) indicate that 5-HT2A agonists modulate the activity of glutamate gated ion channels via NMDA receptors.
  • Arvanov et al. suggest that this modulation of NMDA receptor ionophores is responsible for the mind altering effects of hallucinogenic 5-HT2A agonists.
  • NMDA antagonists also have well known and powerful mind altering effects. Apparently, this ion channel is a centerpiece of the substance matter from which the mind emanates.
  • the discovery of the unique effects on the human mind of a combination of a 5-HT2A agonist and a NMDA antagonist provides additional evidence for the pivotal role of NMDA receptor ionophores in the highest functions of the human brain. And it is a first indication that it might be possible to actually improve the functioning of the brain through pharmacological manipulations at this site.
  • both 5-HT2A agonists and NMDA antagonist modulate NMDA receptor ionophores out of balance, but in opposite directions. This would explain the similar yet distinct effects which 5-HT2A agonists and NMDA antagonist have on the human mind.
  • NMDA receptor ionophores are not modulated out of balance, but are either stabilized in balance, or modulated in a third direction.
  • NMDA antagonist inhibits the development of tolerance towards the effects of the 5-HT2A agonist. This finding resembles the known effect of reduced development of tolerance to the analgesic effects of opioids by concurrent administration of a NMDA antagonist as disclosed in Science 251(4989):85-7, 1991 (PMID: 1824728). Additional research needs to be conducted to elucidate if and how NMDA antagonists inhibit the development of tolerance towards 5-HT2A agonists.
  • NMDA antagonist compound and which 5-HT2A agonist compound is used. It is therefore necessary to conduct further research to identify the most suitable 5-HT2A agonists and NMDA antagonist for the induction of this novel state or mode of the human mind.
  • the induction of this novel mental state may also be used in the treatment of a wide variety of conditions, disorders and diseases, which include, but are not limited to, mental and neurological diseases and disorders, neurodegenerative diseases, drug addiction and withdrawal, pain, cerebral trauma and hypoxia, stroke and epilepsy. Research needs to be conducted to further develop these applications.
  • Alzheimer's disease It is therefore quite likely that other NMDA antagonists are also useful in the treatment of this disease.
  • the Applicant believes that the combination of a NMDA antagonist and a 5-HT2A agonist is particularly useful for the treatment of Alzheimer's disease, because it strengthens and activates the highest functions of the human brain, which are impaired in patients suffering from Alzheimer's disease.
  • the doses are in the same range at which NMDA antagonists have shown neuroprotective properties and were explored in clinical trials for conditions such as stroke and traumatic brain injury. They are also in the same range in which the NMDA antagonist ketamine is used for therapeutic purposes.
  • the Applicant has found that the most suitable and desirable dose of the NMDA antagonist is the threshold dose, or somewhat below the threshold dose, for the induction of psychotomimetic effects.
  • the threshold dose is that dose at which the subject experiences the first psychotomimetic mental alterations caused by an NMDA antagonist, but they are mild and not troublesome. While higher doses, which cause more pronounced psychotomimetic effects, might still be useful in certain cases, they are generally considered less desirable and less suitable for the induction of the disclosed effect.
  • the dose of the 5-HT2A agonist may be varied depending on the individual's response and the desired effect. While lower doses might be sufficient and more desirable in many cases, even high doses of the 5-HT2A agonist, which when administered alone would have a very strong hallucinogenic effect, can be used without causing hallucinations or psychosis.
  • the NMDA antagonist and the 5-HT2A agonist may be administered either simultaneously, or the drugs may be administered sequentially in such a way that their tissue concentrations and pharmacological effects develop uniformly and synchronously. While it is most desirable that the agonistic activity at the 5-HT2A receptor and the antagonistic activity at the NMDA receptor develop uniformly and synchronously, it may in certain cases be advantageous to cause either the 5-HT2A agonistic or NMDA antagonistic effect first, and then cause the other effect thereafter.
  • the NMDA antagonist and the 5-HT2A agonist may be administered in any form which is physiologically compatible.
  • the method of administration may be freely chosen from the many methods known in the art to administer a drug to a human being.
  • a combination of a 5-HT2A agonist and a NMDA antagonist may either be in the form of two compounds, or in the form of one compound which has both 5-HT2A agonistic and NMDA antagonistic activity. Any composition of matter which concurrently has agonistic activity at the 5-HT2A receptor and antagonistic activity at the NMDA receptor is therefore also considered as a combination of a 5-HT2A agonist and a NMDA antagonist.
  • the Applicant was initially interested in exploring the effects of sub-threshold and threshold doses of NMDA antagonists on the human mind. The Applicant therefore needed to obtain a suitable NMDA antagonist for his research. Most NMDA antagonists are either controlled substances and therefore inaccessible for the Applicant, or are difficult to synthesize and therefore beyond the limited means of the Applicant. The Applicant was however able to identify N-ethyl-l,2-diphenylethylamine as a suitable candidate as NMDA antagonist for his research. This compound has been disclosed in NIDA Res Monogr. 1989;95:51-6 (PMID: 2561843) as a reasonably potent NMDA antagonist.
  • K3 The Applicant found K3 to have all the typical effects on the human mind which had to be expected for a NMDA antagonist.
  • the threshold dose where psychotomimetic effects would start to become noticeable, was found to be between 75 mg and 100 mg for an adult human being.
  • the main disadvantages of K3 are the slow onset of activity and the short duration. Effects take about 2 hours to fully develop and last about 4 hours. Concurrent food intake seems to enhance and accelerate the resorption of K3.
  • 5-HT2A agonist known as 2C-D developed by Alexander Shulgin and described in his book PiHKAL. While using small doses of K3 to improve his cognitive abilities, the Applicant decided to further explore the effects of the 5-HT2A agonist 2C-D on his mind. In an experiment conducted on February 2nd, 2006, the Applicant noticed novel and unexpected effects of the 5-HT2A agonist on his mind. Further research and diligent experimentation led to the disclosed discoveries.
  • (+)-MK-801 has been found to be an excellent and clearly superior replacement for
  • (+)-MK-801 A dose of 0.5 mg (+)-MK-801 appears to be equivalent to 75 mg of K3 and is just below the threshold dose.
  • the effects of (+)-MK-801 are well developed at 1 hour after oral administration and last an estimated 6 - 8 hours.
  • (+)-MK-801 can be administered simultaneously with the 5-HT2A agonist, while K3 had to be administered before the 5-HT2A agonist due to its slow onset of activity, which made it difficult to synchronize the effects.
  • Data disclosed by Wender et al. in Psychopharmacol Bull. 22(l):237-42, 1986 (PMID: 3523579) were helpful in finding a suitable dose of (+)-MK-801.
  • 5-MeO-MPMI has been found by the Applicant to have rather unpleasant effects on the human mind and therefore has little potential to become a drug of abuse.
  • the Applicant has found 5-MeO-MPMI to be an excellent 5-HT2A agonist for the induction of the disclosed effect.
  • the most reliable and preferred way to induce the disclosed novel state of mind consists in the oral administration of 0.5 mg (+)-MK-801 as maleate and 2.0 mg 5-MeO-MPMI as free base to an adult human being of 85 kg body weight.
  • the dose of (+)-MK-801 has been found to be rather critical for a smooth induction.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Addiction (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Il a été découvert que l'administration, à un être humain, d'un agoniste de 5-HT2A hallucinogène en combinaison avec un antagoniste de NMDA induisait un état nouveau et particulier du psychisme humain. Cet état psychique est non psychotique et bénin. L'induction de cet état nouveau et particulier du psychisme humain peut être utilisé à des fins thérapeutiques, récréatives et à d'autres fins utiles.
PCT/IB2006/051080 2006-04-09 2006-04-09 Induction d'un nouvel etat psychique a l'aide d'un agoniste de 5-ht2a et d'un antagoniste de nmda WO2006079999A2 (fr)

Priority Applications (1)

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PCT/IB2006/051080 WO2006079999A2 (fr) 2006-04-09 2006-04-09 Induction d'un nouvel etat psychique a l'aide d'un agoniste de 5-ht2a et d'un antagoniste de nmda

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PCT/IB2006/051080 WO2006079999A2 (fr) 2006-04-09 2006-04-09 Induction d'un nouvel etat psychique a l'aide d'un agoniste de 5-ht2a et d'un antagoniste de nmda

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10519175B2 (en) 2017-10-09 2019-12-31 Compass Pathways Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11564935B2 (en) 2019-04-17 2023-01-31 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992006973A1 (fr) * 1990-10-15 1992-04-30 Pfizer Inc. Derives d'indole
US5902815A (en) * 1996-09-03 1999-05-11 Washington University Use of 5HT-2A serotonin agonists to prevent adverse effects of NMDA receptor hypofunction
WO2006042249A2 (fr) * 2004-10-08 2006-04-20 Neuromolecular Pharmaceuticals, Inc. Methodes et compositions de traitement de la douleur de migraine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992006973A1 (fr) * 1990-10-15 1992-04-30 Pfizer Inc. Derives d'indole
US5902815A (en) * 1996-09-03 1999-05-11 Washington University Use of 5HT-2A serotonin agonists to prevent adverse effects of NMDA receptor hypofunction
WO2006042249A2 (fr) * 2004-10-08 2006-04-20 Neuromolecular Pharmaceuticals, Inc. Methodes et compositions de traitement de la douleur de migraine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FARBER NURI B ET AL: "Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity" NEUROPSYCHOPHARMACOLOGY, vol. 18, no. 1, January 1998 (1998-01), pages 57-62, XP002396767 ISSN: 0893-133X *
WEST WILLIAM B ET AL: "Antagonism of a PCP drug discrimination by hallucinogens and related drugs" NEUROPSYCHOPHARMACOLOGY, vol. 22, no. 6, June 2000 (2000-06), pages 618-625, XP002396768 ISSN: 0893-133X cited in the application *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10519175B2 (en) 2017-10-09 2019-12-31 Compass Pathways Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US10947257B2 (en) 2017-10-09 2021-03-16 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US10954259B1 (en) 2017-10-09 2021-03-23 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11149044B2 (en) 2017-10-09 2021-10-19 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11180517B2 (en) 2017-10-09 2021-11-23 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11447510B2 (en) 2017-10-09 2022-09-20 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11505564B2 (en) 2017-10-09 2022-11-22 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11629159B2 (en) 2017-10-09 2023-04-18 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11851451B2 (en) 2017-10-09 2023-12-26 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11939346B2 (en) 2017-10-09 2024-03-26 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11564935B2 (en) 2019-04-17 2023-01-31 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin
US11738035B2 (en) 2019-04-17 2023-08-29 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin

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