Design and Discovery of Functionally Selective Serotonin 2C (5-HT2C) Receptor Agonists. J Med Chem 2016 Nov 10;59(21):9866-9880
Date
10/12/2016Pubmed ID
27726356DOI
10.1021/acs.jmedchem.6b01194Scopus ID
2-s2.0-84994823994 (requires institutional sign-in at Scopus site) 32 CitationsAbstract
On the basis of the structural similarity of our previous 5-HT2C 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-HT2A, 5-HT2B, and 5-HT2C receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT2C 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-HT2C agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.
Author List
Cheng J, McCorvy JD, Giguere PM, Zhu H, Kenakin T, Roth BL, Kozikowski APAuthor
John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Dose-Response Relationship, DrugDrug Discovery
Humans
Molecular Structure
Receptor, Serotonin, 5-HT2C
Serotonin 5-HT2 Receptor Agonists
Structure-Activity Relationship
