Design and Discovery of Functionally Selective Serotonin 2C (5-HT2C) Receptor Agonists

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-11, Vol.59 (21), p.9866-9880
Main Authors: Cheng, Jianjun, McCorvy, John D, Giguere, Patrick M, Zhu, Hu, Kenakin, Terry, Roth, Bryan L, Kozikowski, Alan P
Format: Article
Language:English
Subjects:
Dose-Response Relationship, Drug
Drug Discovery
Humans
Molecular Structure
Receptor, Serotonin, 5-HT2C - metabolism
Serotonin 5-HT2 Receptor Agonists - chemical synthesis
Serotonin 5-HT2 Receptor Agonists - chemistry
Serotonin 5-HT2 Receptor Agonists - pharmacology
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b01194