Probes for narcotic receptor-mediated phenomena.: 27.: Synthesis and pharmacological evaluation of selective δ-opioid receptor agonists from 4-[(αR)-α-(2S,5R)-4-substituted-2,5-dimethyl-1-piperazinyl-3-methoxybenzyl]-N,N-diethylbenzamides and their enantiomers

Potent, selective, and efficacious delta-opioid receptor agonists such as (+)-4-[(alpha R)-alpha-(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl-3-methoxybenzyl]-N,N-diethylbenzamide [SNC80, (+)-2] have been found to be useful tools for exploring the structural requirements which are necessary for ligands which interact with the delta-receptor. To determine the necessity for the 4-allyl moiety in (+)-2, this substituent was replaced with a variety of 4-alkyl, 4-arylalkyl, and 4-alkenyl substituents. The corresponding enantiomers of these compounds were also synthesized. The binding affinities for the mu-, delta-, and kappa-opioid receptors and efficacies in the functional GTP gamma S binding assay were determined for the (+)-2 related compounds and their enantiomers. The 4-crotyl analogue was found to have similar delta-receptor affinity and efficacy as (+)-2, but the 4-cyclopropylmethyl analogue, in the functional assay, appeared to be a partial agonist with little antagonist activity.