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

摘要

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.