Section 48
Chapter 47,080

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

Furness, M.S.; Zhang, X.; Coop, A.; Jacobson, A.E.; Rothman, R.B.; Dersch, C.M.; Xu, H.; Porreca, F.; Rice, K.C.

Journal of Medicinal Chemistry 43(16): 3193-3196


ISSN/ISBN: 0022-2623
PMID: 10956228
DOI: 10.1021/jm0001222
Accession: 047079530

Potent, selective, and efficacious delta-opioid receptor agonists such as (+)-4-[(alphaR)-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 GTPgammaS 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.

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