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 in vitro isolated preparations. N, N-Diallyl-[D-Ala², D-Leu⁵]-enkephalin [test compound I] at doses up to 10 μM 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 K_e (equilibrium dissociation constant) values againsttest 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 K_e values of ICI 154129 against compound I were approximately 340 nM, strongly suggesting that test compound I acted as a delta agonist. The K_e 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 μM, 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.