Semisynthetic Transformations on (+)-Boldine Reveal a 5-HT_2A/2CR Antagonist

Aporphine alkaloids have shown affinity for serotonin receptors (5-HTRs), and there has been a recent upsurge of interest in aporphines as 5-HT_2CR ligands. 1,2,9,10-Tetraoxygenated aporphine alkaloids in particular have demonstrated good affinity for 5-HTRs. In continued efforts to understand the impacts of structural modification of the 1,2,9,10-tetraoxygenated aporphine template on affinity, selectivity, and activity at 5-HT₂R subtypes, we used (+)-boldine (8) as a semisynthetic feedstock in the preparation of C-2-alkoxylated (+)-predicentrine analogues. Compound 10n, which contains a benzyloxy group at C-2, has been identified as a novel 5-HT_2CR ligand with strong affinity (4 nM) and moderate selectivity versus 5-HT_2BR and 5-HT_2AR (12-fold and 6-fold, respectively). Compound 10n functions as an antagonist at 5-HT_2A and 5-HT_2C receptors. Computational experiments indicate that several hydrophobic interactions as well as strong H-bond and salt bridge interactions between the protonated amine moiety in 10n and Asp134 are responsible for the potent 5-HT_2CR affinity of this compound. Furthermore, compound 10n displays favorable predicted drug-like characteristics, which is encouraging toward future optimization.