Synthesisand Evaluation of Novel Aza-Aromatics asDual 5‑HT2A and 5‑HT2C Receptor Agonists
Figshare – November 26, 2025
Source: OpenAlex
Summary
A nonhallucinogenic dual agonist, 3ci, shows promise for treating CNS disorders by selectively targeting the 5-HT2A and 5-HT2C receptors. Out of 22 synthesized compounds, both 3ci and its counterpart 3dh exhibited effective agonist activity with EC50 values under 1 μM and no 5-HT2B activity up to 10 μM. Pharmacokinetic analysis in mice revealed rapid absorption, with peak plasma concentrations reaching 936.4 ng/mL. Notably, both compounds induced a head-twitch response, indicating potential therapeutic benefits with reduced hallucinogenic effects.
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.