A novel Aminotetralin-Type Serotonin (5-HT)2C receptor-specific Agonist and 5-HT2A competitive Antagonist/5-HT2B inverse agonist with preclinical efficacy for Psychoses

Clinton E. Canal, Drake Morgan, Daniel Felsing, Krishnakanth Kondabolu, Neil E. Rowland, Kimberly L. Robertson, Rajeev Sakhuja, Raymond G. Booth

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Development of 5-HT2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT2C selective agonists also activate 5-HT2A and/or 5-HT2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT2C receptor agonist, (2)-trans-(2S,4R)-4-(39[meta]- bromophenyl)- N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-Amine (2)-MBP), that is a competitive antagonist and inverse agonist at human 5-HT2A and 5-HT2B receptors, respectively. (2)-MBP has efficacy comparable to the prototypical second-generation antipsychotic drug clozapine in three C57Bl/6 mouse models of drug-induced psychoses: the head-twitch response elicited by [2,5]-dimethoxy- 4-iodoamphetamine; hyperlocomotion induced by MK-801 [(5R, 10S)-(1)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine hydrogen maleate (dizocilpine maleate)]; and hyperlocomotion induced by amphetamine. (2)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (2)-MBP at a dose that produced at least 50%maximal efficacy in the psychoses models. Compared with (2)-MBP, the enantiomer (1)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT2C receptor-specific agonist, such as (2)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders.

Original languageEnglish (US)
Pages (from-to)310-318
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume349
Issue number2
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Serotonin 5-HT2 Receptor Agonists
Receptor, Serotonin, 5-HT2C
Serotonin 5-HT2 Receptor Antagonists
Receptor, Serotonin, 5-HT2B
Psychotic Disorders
Serotonin
Dizocilpine Maleate
Clozapine
Hallucinations
Locomotion
Obesity
Substance-Induced Psychoses
Imines
Amphetamine
Antipsychotic Agents
Substance-Related Disorders
Amines
Heart Diseases
Head
Food

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

A novel Aminotetralin-Type Serotonin (5-HT)2C receptor-specific Agonist and 5-HT2A competitive Antagonist/5-HT2B inverse agonist with preclinical efficacy for Psychoses. / Canal, Clinton E.; Morgan, Drake; Felsing, Daniel; Kondabolu, Krishnakanth; Rowland, Neil E.; Robertson, Kimberly L.; Sakhuja, Rajeev; Booth, Raymond G.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 349, No. 2, 01.01.2014, p. 310-318.

Research output: Contribution to journalArticle

Canal, Clinton E. ; Morgan, Drake ; Felsing, Daniel ; Kondabolu, Krishnakanth ; Rowland, Neil E. ; Robertson, Kimberly L. ; Sakhuja, Rajeev ; Booth, Raymond G. / A novel Aminotetralin-Type Serotonin (5-HT)2C receptor-specific Agonist and 5-HT2A competitive Antagonist/5-HT2B inverse agonist with preclinical efficacy for Psychoses. In: Journal of Pharmacology and Experimental Therapeutics. 2014 ; Vol. 349, No. 2. pp. 310-318.
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abstract = "Development of 5-HT2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT2C selective agonists also activate 5-HT2A and/or 5-HT2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT2C receptor agonist, (2)-trans-(2S,4R)-4-(39[meta]- bromophenyl)- N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-Amine (2)-MBP), that is a competitive antagonist and inverse agonist at human 5-HT2A and 5-HT2B receptors, respectively. (2)-MBP has efficacy comparable to the prototypical second-generation antipsychotic drug clozapine in three C57Bl/6 mouse models of drug-induced psychoses: the head-twitch response elicited by [2,5]-dimethoxy- 4-iodoamphetamine; hyperlocomotion induced by MK-801 [(5R, 10S)-(1)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine hydrogen maleate (dizocilpine maleate)]; and hyperlocomotion induced by amphetamine. (2)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (2)-MBP at a dose that produced at least 50{\%}maximal efficacy in the psychoses models. Compared with (2)-MBP, the enantiomer (1)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT2C receptor-specific agonist, such as (2)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders.",
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