(R)-11-HYDROXY-METHYLAPOPHINE AND (R)-11-HYDROXY-1O-METHYLAPORPHINE -SYNTHESIS, PHARMACOLOGY, AND MODELING OF D-2A AND 5-HT1A RECEPTOR INTERACTIONS

(R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natural morphine by using new, short, and effici ent synthetic sequences. The dopaminergic and serotonergic effects of 2 and 3 were evaluated by use of in vitro and in vivo test systems. Th e results indicate that 3 is a potent, selective, and efficacious 6-HT 1A receptor agonist. In contrast, 2 is a partial 5-HT1A receptor agoni st of low potency which has affinity also for central D-1 and D-2A rec eptors. The differences in pharmacological profiles were rationalized by modeling of ligand-receptor interactions using homology-based recep tor models of the 6-HT1A and D-2A receptor binding site. The selective and pronounced serotonergic effects of 3 appear to be due to the CIO- 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 accommodate d by the binding site model of the D-2A receptor.