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

Jianjun Cheng, John D. McCorvy, Patrick M. Giguere, Hu Zhu, Terry Kenakin, Bryan L. Roth, Alan P. Kozikowski

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)9866-9880
Number of pages15
JournalJournal of medicinal chemistry
Issue number21
StatePublished - Nov 10 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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