ENANTIOMERIC N-SUBSTITUTED N-NORMETAZOCINES - A COMPARATIVE-STUDY OF AFFINITIES AT SIGMA, PCP, AND MU OPIOID RECEPTORS

The optical antipodes of N-allyl-N-normetazocine (2; SKF 10047, NANM) were the original compounds used for the classification of the sigma-receptor as distinct from other receptors such as the PCP (NMDA), opioid, and dopamine receptors. Later studies showed that (+)-N-(dimethylallyl)-N-normetazocine [(+)-4, (+)-pentazocine] was more potent and selective for the sigma-receptor. In order to gain additional structure-activity relationship information, several N-substituted N-normetazocine analogs were prepared and evaluated for their sigma-1 ([H-3]-(+)-3-PPP or [H-3]-(+)-pentazocine), PCP ([H-3]TCP), and mu-opioid ([H-3]DAMGO) receptor binding affinities. (+)-N-Benzyl-N-normetazocine [(+)-10)] possessed subnanomolar affinities for the sigma-site, K(i) = 0.67. The analog (+)-10 showed > 14000- and 2400-fold selectivity, respectively, for the sigma-receptor relative to the PCP and mu-opioid receptors. The N-substituted N-normetazocines were enantioselective for the sigma-site. The (+)-N-benzyl analog, (+)-10, showed a 55-fold selectivity relative to (-)-10. Analysis of the data also revealed that (+)-normetazocine [(+)-1] [K(i) = 30 nM] possessed the highest affinity for the PCP receptor. However, (+)-metazocine [(+)-5] (K(i) = 41 nM) was the most selective compound for the PCP receptor relative to the sigma (51-fold) and mu-opioid (> 200-fold) sites.