Synthesis and binding studies of 2-O- and 11-O-substituted N-alkylnoraporphines

We synthesized several novel 2-O- or 11-O-substituted N-alkylnoraporphines and assessed their affinities at dopamine D1 and D2, and serotonin 5-HT1A receptors in rat forebrain tissue. Tested compounds displayed moderate to high affinities to D2 receptors but low affinities to D1 and 5HT1A receptors. The findings accord with previous evidence of a lipophilic cavity on the surface of the D2 receptor to accommodate N-alkyl moieties of aporphines. The most D2-potent (Ki = 97 nM) and selective novel agent (>100-fold vs. D1 and 5-HT1A sites) was R(−)-2-(2-hydroxyethoxy)-11-hydroxy-N-n-propylnoraporphine (compound 11).