Opiate receptor subclasses differ in their conformational requirements

Abstract

Pharmacological and biochemical studies of classical opiates and opioid peptide analogues have revealed the existence of several subclasses of opiate receptors^1–5, among which the μ-, δ-, κ- and σ-receptors have been most widely discussed. The physiological roles of the different receptor classes and their structural characteristics remain to be elucidated. Recently, a cyclic analogue of enkephalin, H-Tyr-cyclo[-N^γ-D-A₂bu-Gly-Phe-Leu-] (Fig. 1, compound I; A²bu represents α,γ-diamino-butyric acid), showing high potency in μ-receptor-selective bio- and binding assays has been described⁶. To assess the effect of the conformational constraint introduced by cyclization on opiate receptor selectivity, we have compared the cyclic compound I with its corresponding open-chain analogue, [D-Abu²,Leu⁵]enkephalinamide (Fig. 1, compound II; Abu represents α-aminobutyric acid), in bioassays based on inhibition of electrically evoked contractions of the guinea pig ileum and the mouse vas deferens, and in binding assays using μ-and σ-receptor-selective radiolabels. The differences in potency of the two compounds observed in the four assay systems suggest that the various opiate receptor subclasses have different preferences in terms of conformational properties of ‘complementary’ ligands.