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

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Abstract
Potent, selective, and efficacious δ-opioid receptor agonists such as (+)-4-[(αR)-α-(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 δ-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 μ-, δ-, and κ-opioid receptors and efficacies in the functional GTPγS binding assay were determined for the (+)-2 related compounds and their enantiomers. The 4-crotyl analogue was found to have similar δ-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.