Synthesis and Evaluation of Novel Aza-Aromatics as Dual 5-HT2A and 5-HT2C Receptor Agonists

The 5-HT2A and 5-HT2C receptors are key therapeutic targets for CNS disorders. We investigated whether a nonhallucinogenic dual 5-HT2A/5-HT2C agonist could offer novel treatment potential. Large screening of in-house structurally diverse compounds revealed centhaquin, an FDA-approved hypovolemic shock drug, as a selective 5-HT2C agonist (EC50: 35 nM). We then synthesized 22 aza-aryl analogs with modified piperazine groups, and identified two dual agonists, <b>3ci</b> and <b>3dh</b> (EC50 < 1 μM), with no 5-HT2B activity up to 10 μM. Molecular docking highlighted critical interactions with Ser159 (5-HT2A) and Ser138 (5-HT2C) on the upper side of the orthosteric binding pocket. Pharmacokinetic studies in mice demonstrated that <b>3ci</b> was rapidly absorbed in the plasma and brain (<i>T</i> _max = 0.08 h; <i>C</i> _max = 936.4 ng/mL plasma, 2446.8 ng/g brain). Both compounds (<b>3ci</b> and <b>3dh</b>, 20 mg/kg, <i>i.p.</i>) triggered a head-twitch response but were less potent than the hallucinogenic control 2,5-dimethoxy-4-iodoamphetamine, suggesting a reduced hallucinogenic liability. These results highlight <b>3ci</b> as a promising lead for developing 5-HT2A/2C dual agonists to treat CNS disorders.