title: Two new opioid delta-receptor ligands: a highly selective agonist and a potent selective antagonist in in vitro isolated preparations.
abstract: N,N-Diallyl derivatives of enkephalin analogues were chemically synthesized, and their biological activities were estimated in vitro isolated preparations. N,N-Diallyl-[D-Ala2, D-Leu5]-enkephalin [test compound I] at doses up to 10 microM did not inhibit the electrically-evoked contractions of guinea-pig ileum, which had been suggested to contain opioid mu- and kappa-receptors, but it significantly depressed the contractions of mouse vas deferens, which had been indicated to contain mu-, kappa- and delta-receptors, suggesting that test compound I did not act on both mu- and kappa-receptors, but acted on delta-receptors. Additionally, the Ke (equilibrium dissociation constant) values against test compound I of naloxone were approximately 30 nM and similar to those of Mr 2266, also indicating that test compound I acted as a delta agonist. Moreover, the Ke values of ICI 154129 against compound I were approximately 340 nM, strongly suggesting that test compound I acted as a delta agonist. The Ke values of bis-[N,N-diallyl-[D-Ala2, Leu5]-enkephalyl]-cystine [test compound II] against [D-Ala2, D-Leu5]-enkephalin in mouse vas deferens and morphine or ethylketocyclazocine in guinea-pig ileum were 44.9 nM and 5.00 or 11.3 microM, respectively, showing that test compound II was a potent selective opioid delta antagonist. In conclusion, among compounds synthesized, two new opioid delta-receptor ligands, one being a highly selective agonist and the other being a potent selective antagonist in in vitro isolated preparations, were found in the present study.
mesh_terms: D000818:Animals; D001575:Benzomorphans / Q000494:pharmacology; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine / Q000031:analogs & derivatives*; D004745:Enkephalins / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D001575:Benzomorphans; D004745:Enkephalins; D008024:Ligands; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D009270:Naloxone; C027247:MR 2266; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; C031733:enkephalin, Ala(2)-Val(5)-; C044717:enkephalin-Leu, N,N-diallyl-Ala(2)-; C044718:enkephalin-Leu, N,N-diallyl-Ala(2)-bis(cystine)(6)-; C036405:ICI 154129