Synthesis and dopamine receptor affinities of N-alkyl-11-hydroxy-2-methoxynoraporphines:: N-alkyl substituents determine D1 versus D2 receptor selectivity

We developed a procedure to synthesize a series of N-alkyl-2-methoxy-11-hydroxyhoraporphines from thebaine and evaluated their binding affinities at dopamine D-1 and D-2 receptors in rat forebrain tissue. At D-2 receptors, the most potent 10,11-catechol-aporphine was (R)-(-)-2-methoxy-N-n-propylnorapomorphine (D-2, K-i = 1.3 nM; D-1, K-i = 6450 nM), and the most selective and potent 11-monohydroxy aporphine was (R)-(-)-2-methoxy-11-hydroxy-N-n-propylnoraporphine (D-2, K-i = 44 nM; D-1, K-i = 1690 nM). In contrast, the N-methyl congeners (R)-(-)-2-methoxy-11-hydroxy: N-methyl-aporphine (D-1 vs D-2, K-i = 46 vs 235 nM) showed higher D-1 than D2 affinity, indicating that N-alkyl substituents have major effects on D2 affinity and D-2/D-1 selectivity in such 2-methoxy-11-monohydroxy-substituted aporphines.