RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.113.212373
DO 10.1124/jpet.113.212373
A1 Clinton E Canal
A1 Drake Morgan
A1 Daniel Felsing
A1 Krishnakanth Kondabolu
A1 Neil E. Rowland
A1 Kimberly L. Robertson
A1 Rajeev Sakhuja
A1 Raymond G. Booth
YR 2014
UL http://jpet.aspetjournals.org/content/early/2014/02/21/jpet.113.212373.abstract
AB 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, (-)-trans-(2S,4R)-4-(3'[meta]-bromophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine ((-)-MBP), that is a competitive antagonist and inverse agonist at human 5-HT2A and 5-HT2B receptors, respectively. In three C57Bl/6 mouse models of drug-induced psychoses ([2,5]-dimethoxy-4-iodoamphetamine elicited head-twitch response, MK-801-induced hyperlocomotion, and amphetamine-induced hyperlocomotion), (-)-MBP has efficacy comparable to the prototypical second-generation antipsychotic drug, clozapine. (-)-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 (-)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared to (-)-MBP, (+)-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 (-)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation or motoric disorders.