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 D(1) and D(2), and serotonin 5-HT(1A) receptors in rat forebrain tissue. Tested compounds displayed moderate to high affinities to D(2) receptors but low affinities to D(1) and 5HT(1A) receptors. The findings accord with previous evidence of a lipophilic cavity on the surface of the D(2) receptor to accommodate N-alkyl moieties of aporphines. The most D(2)-potent (K(i)=97 nM) and selective novel agent (>100-fold vs. D(1) and 5-HT(1A) sites) was R(-)-2-(2-hydroxyethoxy)-11-hydroxy-N-n-propylnoraporphine (compound 11).