Discovery of New N‑H Aporphine Derivatives As Brain-Penetrant Gq‑Biased 5‑HT2C Receptor Agonists and Dual 5‑HT2C/5-HT2A Receptor Agonists

The 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR) are located in the brain and play overlapping roles in modulating mood, stress, learning, etc. Recently, 5-HT2CR and/or 5-HT2AR agonists have garnered renewed interest for the central nervous system (CNS) drug discovery, with several candidates advanced into clinical trials. A molecular hybridization strategy was utilized to design and synthesize two series of new N-H aporphines with improved 5-HT2CR potency and selectivity. Most of 2,11-disubstituted derivatives (e.g., 16l, 20n) in series II showed potent 5-HT2CR/5-HT2AR dual agonistic activity. Notably, 1,2,11-trisubstituted aporphine 16k was identified as the most selective and Gq-biased 5-HT2CR agonist, exhibiting low nanomolar potency and high selectivity for the 5-HT2A/2B/2C subfamily, as well as good brain exposure and penetration, thus reversing MK801- and PCP-induced hyperlocomotion. These newly discovered selective 5-HT2CR agonists and 5-HT2CR/5-HT2AR dual agonists will broaden the toolbox to facilitate the biological research of these vital receptors and the development of novel CNS candidates.