2. Academic Validation
  3. Synthesis and Evaluation of Novel Aza-Aromatics as Dual 5‑HT2A and 5‑HT2C Receptor Agonists

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

  • ACS Med Chem Lett. 2025 Nov 26;16(12):2435-2443. doi: 10.1021/acsmedchemlett.5c00505.
Amit Singh Adhikari 1,  Annu Yadav 2 3,  Soumen Pandit 1,  Suresh Kumar 1 3 4,  Vinay Kumar Pandey 1,  Arvind Kumar Maurya 1 3,  Deepmala Umrao 2,  Diwan Chand 1 3,  Debalina Maity 5 3,  Jiaur R Gayen 5 3,  Kinshuk Raj Srivastava 1 3,  Prem N Yadav 2 3,  Nilanjana Majumdar 1 3 4
Affiliations

Affiliations

  • 1 Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh, India.
  • 2 Division of Neuroscience & Ageing Biology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh, India.
  • 3 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India.
  • 4 Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL), Pune 411008, Maharashtra, India.
  • 5 Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh, India.
PMID: 41404005 DOI: 10.1021/acsmedchemlett.5c00505
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 < 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 3ci was rapidly absorbed in the plasma and brain (T max = 0.08 h; C max = 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.

Keywords

5-HT2A; 5-HT2C; Centhaquin; GPCR; Head Twitch Response; Serotonin Receptor.

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