Design and Discovery of Functionally Selective Serotonin 2C (5-HT) Receptor Agonists.
Basic Information
ID: ALA4680082
Journal: J Med Chem
Title: Design and Discovery of Functionally Selective Serotonin 2C (5-HT) Receptor Agonists.
Authors: Cheng J,McCorvy JD,Giguere PM,Zhu H,Kenakin T,Roth BL,Kozikowski AP
Abstract: On the basis of the structural similarity of our previous 5-HT agonists 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-HT, 5-HT, and 5-HT receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT agonists. 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-HT agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.
CiteXplore: 27726356
DOI: 10.1021/acs.jmedchem.6b01194
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