The optical antipodes of iV-allyl-N-normetazocine (2; SKF 10047, NANM) were the original compounds used for the classification of the a receptor as distinct from otherreceptors 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 a receptor. In order to gain additional structure-activity relationship information, several N-substituted N-normetazocineanalogs were prepared and evaluated for their< rl ([3H]-(+)-3-PPP or [3H]-(+)-pentazodne), PCP ([3H] TCP), and p opioid ([^ JDAMGO) receptor binding affinities.(-t-)-N-Benzyl-iV-normetazocine [(+)-10)] possessed subnanomolar affinities for the a site, K,= 0.67. The analog (+)-10 showed> 14000-and 2400-fold selectivity, respectively, for the a receptor relative to the PCP and p opioid receptors. TheN-substituted N-normetazocines were enantioselective for the a site. The (-t-)-N-benzyl analog,(+)-10, showed a 55-fold selectivity relative to (-)-10. Analysis of the data also revealed that (+)-normetazocine [(+)-l][K;= 30 nM] possessed the highest affinity for the PCP receptor. However,(-l-)-metazocine [(+)-5](K;= 41 nM) was the most selective compound for the PCP receptor relative to the a (51-fold) and p opioid (> 200-fold) sites. iV-Alkyl-substituted analogs of m-(±)-N-normetazocine (1) such as JV-allyl-JV-normetazocine [2,(±)-SKF 10,047, NANM], cyclazocine (3), and pentazocine (4) are reported to produce psychotomimetic effects in animals and in humans. 1" 3 A a (opiate) receptor subtype was postulated by Martin et al. 3 in 1976 to account for the psychotomimetic actions of (±)-SKF 10,047. Since the (-)-isomers of N-substituted N-normetazocines bind much stronger to p and k opiate receptors than the (+)-isomers, the beha-vioral effects of the compounds could be due to the interaction of the (-)-isomer at these opiate receptors. 4, 5 However, the low affinity of (+)-SKF 10,047 for the p and k opiate receptors, 4" 6 combined with the observation that most of the behavioral effect of (+)-SKF 10,047 cannot be antagonized by naloxone7***" 11 suggested that other receptors may be responsible for the behavioral effects of (+)-SKF 10,047. Several studies have revealed three types of re-ceptor interaction:(-)-SKF 10,047 binds primarily to p and k opiate receptors; 12 (+)-SKF 10,047 binds to the phencyclidine (PCP) site of the N-methyl-D-aspartate (NMDA) receptor complex13 and to a non-opiate site that retains the designation a receptor. 6, 14" 16 Little is known about the functions of this distinct a binding site, but available data suggest it may underlie certain motor and perhaps antipsychotic effects of neuroleptics. 17, 18 Furthermore, the existence of at least two putative subtypes (al and (7-2) of a binding sites has further complicated the picture. 19, 20 A paucity of selective ligands with high affinity for a sites has stymied progress toward understanding their functions and potential role in novel ther-apies for psychiatric or neurological disease. Such com-pounds would also be useful for biochemical and neuro-physiological investigations. Toward these goals, we present here the synthesis and receptor binding properties of several (+)-and (-)-N-substituted N-normetazocine analogs. Results Chemistry.(-)-(lfi, 5R, 9R)-and (+)-(lS, 5S, 9S)-N-normetazocine,(-)-l and (+)-l, respectively, were the