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 compounds were evaluated for their selectivity toward 5-HT2A, 5-HT2B, and 5HT(2c) 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 beta-arrestin recruitment. The most functionally selective compound (+)-7e produced weak beta-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 beta-arrestin recruitment can produce distinct receptor desensitization properties.