Aporphines. 39. Synthesis, dopamine receptor binding, and pharmacological activity of (R)-(-)- and (S)-(+)-2-hydroxyapomorphine

Abstract

The enantiomers (6aR and 6aS) of 2,10,11-trihydroxyaporphine (THA) were synthesized from thebaine and bulbocapnine and evaluated pharmacologically in vitro in comparison with (-)-apomorphine [(-)-APO] and dopamine. Competition with tritiated apomorphine, ADTN [2-amino-dihyroxytetrahydronaphthalene] and spiroperidol for binding to a membrane fraction of calf caudate nucleus was evaluated, as well as ability to stimulate adenylate cyclase. In all 4 tests, the rank order of potency was (-)-APO > (-)-THA .mchgt. (+)-THA. Apparently, the 6aR configuration for hydroxyaporphines is preferred for interactions with putative dopamine receptors and 2-hydroxylation reduces potency in comparison with 10,11-dihydroxyaporphines.