Enantiomeric N-Substituted N-Normetazocines: A Comparative Study of Affinities at ?, PCP, and μ Opioid Receptors

Article abstract of DOI:10.1021/jm00093a014

The optical antipodes of N-allyl-N-normetazocine (2; SKF 10047, NANM) were the original compounds used for the classification of the ? 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 ? receptor.In order to gain additional structure-activity relationship information, several N-substituted N-normetazocine analogs were prepared and evaluated for their ?-1 (<3H>-(+)-3-PPP or <3H>-(+)-pentazocine), PCP (<3H>TCP), and μ opioid (<3H>DAMGO) receptor binding affinities. (+)-N-Benzyl-N-normetazocine <(+)-10> possessed subnanomolar affinities for the ? site, K_i = 0.67.The analog (+)-10 showed >14000- and 2400-fold selectivity, respectively, for the ? receptor relative to the PCP and μ opioid receptors.The N-substituted N-normetazocines were enantioselective for the ? site.The (+)-N-benzyl analog, (+)-10, showed a 55-fold selectivity relative to (-)-10.Analysis of the data also revealed that (+)-normetazocine <(+)-1> 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 ? (51-fold) and μ opioid (> 200-fold) sites.