Synthesisand Evaluation of Novel Aza-Aromatics asDual 5‑HT2A and 5‑HT2C Receptor Agonists

A nonhallucinogenic dual 5-HT2A/5-HT2C agonist could offer novel treatment potential for CNS disorders. Screening of in-house compounds revealed centhaquin, an FDA-approved hypovolemic shock drug, as a selective 5-HT2C agonist (EC50: 35 nM). Synthesis of 22 aza-aryl analogs identified two dual agonists, 3ci and 3dh. Compound 3ci was rapidly absorbed in plasma and brain (Tmax = 0.08 h; Cmax = 936.4 ng/mL plasma, 2446.8 ng/g brain). Both compounds triggered a head-twitch response but were less potent than the hallucinogenic control, suggesting reduced hallucinogenic liability. These results highlight 3ci as a promising lead for developing 5-HT2A/2C dual agonists.

Study at a glance

Abstract

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, 3ci and 3dh (EC50 3ci was rapidly absorbed in the plasma and brain (Tmax = 0.08 h; Cmax = 936.4 ng/mL plasma, 2446.8 ng/g brain). Both compounds (3ci and 3dh, 20 mg/kg, i.p.) 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 3ci as a promising lead for developing 5-HT2A/2C dual agonists to treat CNS disorders.