Discovery of New <i>N</i> -H Aporphine Derivatives As Brain-Penetrant G _q -Biased 5-HT _2C Receptor Agonists and Dual 5-HT _2C /5-HT _2A 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 <i>N</i>-H aporphines with improved 5-HT_2CR potency and selectivity. Most of 2,11-disubstituted derivatives (e.g., <b>16l</b>, <b>20n</b>) in series II showed potent 5-HT_2CR/5-HT_2AR dual agonistic activity. Notably, 1,2,11-trisubstituted aporphine <b>16k</b> 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_{2<i>A</i>/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.