title: 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.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, Building 8, Room B1-22, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0815, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Furness
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Coop
authors.forename: A E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: R B
authors.initials: RB
authors.lastname: Rothman
authors.forename: C M
authors.initials: CM
authors.lastname: Dersch
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.forename: F
authors.initials: F
authors.lastname: Porreca
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D009292:Narcotic Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D008024:Ligands; D009292:Narcotic Antagonists; D010879:Piperazines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D016244:Guanosine 5'-O-(3-Thiotriphosphate)