Probes for Narcotic Receptor Mediated Phenomena. 23.1 Synthesis, Opioid Receptor Binding, and Bioassay of the Highly Selective δ Agonist (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]- N,N-diethylbenzamide (SNC 80) and Related Novel Nonpeptide δ Opioid Receptor Ligands

The highly selective delta (δ) opioid receptor agonist SNC 80 [(+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide, (+)-21] and novel optically pure derivatives were synthesized from the enantiomers of 1-allyl-trans-2,5-dimethylpiperazine (2). The piperazine (±)-2 was synthesized, and its enantiomers were obtained on a multigram scale in >99% optical purity by optical resolution of the racemate with the camphoric acids. The absolute configuration of (+)-2 was determined 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 relative configuration of compounds (−)-21, (−)-22, and (+)-23 were obtained by single-crystal X-ray analysis, the assignment of the absolute stereochemistry of the entire series could be made. Radioreceptor binding studies in rat brain preparations showed that methyl ethers (+)-21 (SNC 80) and (−)-25 exhibited strong selectivity for rat δ receptors with low nanomola...