Conformationally constrained cyclic enkephalin analogs with pronounced delta opioid receptor agonist selectivity.
The enkephalin analogs, [D-Pen2,L-Cys5]- and [D-Pen2,D-Cys5]-enkephalin are cyclic compounds, conformationally constrained by virtue of their 14-membered, disulfide containing rings and by the rigidizing effect of the beta, beta dimethyl substituents of the penicillamine side chain. The analogs exhibit profound delta receptor specificity as assessed by their relative potencies in the guinea pig ileum (GPI) and mouse vas deferens (MVD) assays, exhibiting, respectively, 666 and 215 times higher potency in the latter assay system. By contrast, the receptor selectivities measured in rat brain binding assays in the absence of sodium were much more modest, the cyclic analogs being, respectively, 15.2 and 6.0 times more effective at displacing [3H] [D-Ala2,D-Leu5]enkephalin than [3H]naloxone. However, for binding assays performed in the presence of a sodium concentration equivalent to that used in the GPI and MVD assays, these binding selectivities increased to 167 and 49, respectively.
D000818:Animals; D001681:Biological Assay; D001921:Brain / Q000378:metabolism; D004745:Enkephalins / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D011487:Protein Conformation; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000502:physiology
D004745:Enkephalins; D011957:Receptors, Opioid; C038233:enkephalin, Pen(2)-Cys(5)-