title: 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.
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, (-)-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. (-)-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)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine maleate)]; and hyperlocomotion induced by amphetamine. (-)-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 with (-)-MBP, the enantiomer (+)-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.
authors.affiliation: Center for Drug Discovery (C.E.C., R.G.B.), Department of Pharmaceutical Sciences (C.E.C., R.G.B.), and Department of Chemistry and Chemical Biology (R.G.B.), Northeastern University, Boston, Massachusetts; Department of Psychiatry (D.M.), Medicinal Chemistry (D.F., R.S., K.K., R.G.B.), and Psychology (N.E.R., K.L.R.), University of Florida, Gainesville, Florida.
authors.forename: Clinton E
authors.initials: CE
authors.lastname: Canal
authors.forename: Drake
authors.initials: D
authors.lastname: Morgan
authors.forename: Daniel
authors.initials: D
authors.lastname: Felsing
authors.forename: Krishnakanth
authors.initials: K
authors.lastname: Kondabolu
authors.forename: Neil E
authors.initials: NE
authors.lastname: Rowland
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Robertson
authors.forename: Rajeev
authors.initials: R
authors.lastname: Sakhuja
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Booth
mesh_terms: D015081:2-Naphthylamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D005247:Feeding Behavior / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006948:Hyperkinesis / Q000188:drug therapy / Q000209:etiology; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D011618:Psychotic Disorders / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D011869:Radioligand Assay; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: C000589465:4-(3'-bromophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine; D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D000661:Amphetamine; D015081:2-Naphthylamine