(R)-11-Hydroxy- and (R)-11-Hydroxy-10-methylaporphine: Synthesis, Pharmacology, and Modelling of D2A and 5-HT1A Receptor Interactions

Article abstract of DOI:10.1021/jm00004a011

(R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natural morphine by using new, short, and efficent synthetic sequences.The dopaminergic and serotonergic effects of 2 and 3 were evaluated by use of in vitro and in vivo test systems.The results indicate that 3 is a potent, selective, and efficacious 5-HT_1A receptor agonist.In contrast, 2 is a partial 5-HT_1A receptor agonist of low potency which has affinity also for central D₁ and D_2A receptors.The differences in pharmacological profiles were rationalized by modeling of ligand-receptor interactions using homology-based receptor models of the 5-HT_1A and D_2A receptor binding site.The selective and pronounced serotonergic effects of 3 appear to be due to the C10-methyl group, which is accommodated by a lipophilic pocket in the 5-HT_1A receptor.In contrast, the C10-methyl group of 3 is not accommodated by the binding site model of the D_2A receptor.