title: Design and Discovery of Functionally Selective Serotonin 2C (5-HT2C) Receptor Agonists.
abstract: On the basis of the structural similarity of our previous 5-HT2Cagonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT2A, 5-HT2B, and 5-HT2Creceptors in the calcium flux assay with the ultimate goal to generate selective 5-HT2Cagonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT2Cagonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Cheng
authors.forename: John D
authors.initials: JD
authors.lastname: McCorvy
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Giguere
authors.forename: Hu
authors.initials: H
authors.lastname: Zhu
authors.forename: Terry
authors.initials: T
authors.lastname: Kenakin
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists