@article {49879,
	title = {Synthesis and evaluation of novel aza-aromatics as dual 5-HT2A and 5-HT2C receptor agonists},
	journal = {ACS Medicinal Chemistry Letters},
	volume = {16},
	year = {2025},
	month = {DEC },
	pages = {2435-2443},
	type = {Article},
	abstract = {<p>
	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 \&lt; 1 mu M), with no 5-HT2B activity up to 10 mu M. 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.</p>
},
	keywords = {5-HT2A, 5-HT2C, Centhaquin, GPCR, Head Twitch Response, Serotonin Receptor},
	issn = {1948-5875},
	doi = {10.1021/acsmedchemlett.5c00505},
	author = {Adhikari, Amit Singh and Yadav, Annu and Pandit, Soumen and Kumar, Suresh and Pandey, Vinay Kumar and Maurya, Arvind Kumar and Umrao, Deepmala and Chand, Diwan and Maity, Debalina and Gayen, Jiaur R. and Srivastava, Kinshuk Raj and Yadav, Prem N. and Majumdar, Nilanjana}
}
