PROBES FOR NARCOTIC RECEPTOR-MEDIATED PHENOMENA .23. SYNTHESIS, OPIOID RECEPTOR-BINDING, AND BIOASSAY OF THE HIGHLY SELECTIVE DELTA-AGONISTPIPERAZINYL)-3-METHOXYBENZYL]-N,N-DIETHYLBENZAMIDE (SNC-80) AND RELATED NOVEL NONPEPTIDE DELTA-OPIOID RECEPTOR LIGANDS())

The highly selective delta (delta) opioid receptor agonist SNC 80 [(+) -4-[(alpha iperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide, (+)-21] and novel optically pure derivatives were synthesized from the enantio mers of 1-allyl-trans-2,5-dimethylpiperazine (2). The piperazine (+/-) -2 was synthesized, and its enantiomers were obtained on a multigram s cale in > 99% optical purity by optical resolution of the racemate wit h the camphoric acids. The absolute configuration of (+)-2 was determi ned to be 2S,5R by X-ray analysis of the salt with (+)-camphoric acid. Since the chirality of the starting material was known, and the relat ive configuration of compounds (-)-21, (-)-22, and (+)-23 were obtaine d by single-crystal X-ray analysis, the assignment of the absolute ste reochemistry of the entire series could be made. Radioreceptor binding studies in rat brain preparations showed that methyl ethers (+)-21 (S NC 80) and (-)-25 exhibited strong selectivity for rat delta receptors with low nanomolar affinity to delta receptors and only micromolar af finity for rat mu (mu) opioid receptors. Compounds (-)-21, (-)-22, and (-)-23 showed micromolar affinities for mu opioid receptors. The unsu bstituted derivative (+)-22 and the fluorinated derivative (-)-27 show ed >2659- and >2105-fold delta/mu binding selectivity, respectively. T he latter derivatives are the most selective ligands described in the new series. Studies with some of the compounds described in the isolat ed mouse vas deferens and guinea pig ileum bioassays revealed that all were agonists with different degrees of selectivity for the delta opi oid receptor. These data show that (+)-21 and (+)-22 are potent delta receptor agonists and suggest that these compounds will be valuable to ols for further study of the delta opioid receptor at the molecular le vel, including its function and role in analgesia and drug abuse.