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-HT_2A receptor (5-HT_2AR) and 5-HT_2C receptor (5-HT_2CR) are located in the brain and play overlapping roles in modulating mood, stress, learning, etc. Recently, 5-HT_2CR and/or 5-HT_2AR 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-HT_2CR potency and selectivity. Most of 2,11-disubstituted derivatives (e.g., 16l, 20n) in series II showed potent 5-HT_2CR/5-HT_2AR dual agonistic activity. Notably, 1,2,11-trisubstituted aporphine 16k was identified as the most selective and G_q-biased 5-HT_2CR agonist, exhibiting low nanomolar potency and high selectivity for the 5-HT_2A/2B/2C subfamily, as well as good brain exposure and penetration, thus reversing MK801- and PCP-induced hyperlocomotion. These newly discovered selective 5-HT_2CR agonists and 5-HT_2CR/5-HT_2AR dual agonists will broaden the toolbox to facilitate the biological research of these vital receptors and the development of novel CNS candidates.