N,N-diallyl-tyrosyl substitution confers antagonist properties on the κ-selective opioid peptide [D-Pro10]dynorphin A(1-11)

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Abstract
1 In the search for κ-opioid antagonists, we have designed two N,N-diallyl substituted analogues of the κ-selective peptide [D-Pro10]dynorphin A (1–11)(DPDYN). In this study, we have examined (i) the binding properties of N,N-diallyl-DPDYN (analogue 1) and N,N-diallyl-[Aib2,3]DPDYN (analogue 2) at the three main types (μ, δ, κ) of opioid binding sites, (ii) their binding sensitivity to Na+ ions (120 mM NaCl) and guanine nucleotide (50 μm Gpp(NH)p) at μ- and κ-binding sites and (iii) their biological activity in two pharmacological bioassays specific for μ- and κ-(guinea-pig ileum) and κ-(rabbit vas deferens) opioid receptors. 2 Steric hindrance resulting from incorporation of two bulky allyl groups at the tyrosyl nitrogen atom greatly altered the binding properties of DPDYN. A dramatic fall in apparent affinity for the three types (μ, δ, κ) of site as well as selectivity for κ-sites was observed for the two N,N-diallyl-substituted peptide analogues. 3 At κ-sites of guinea-pig cerebellum and μ-sites of rabbit cerebellum, N,N-diallyl-substitution led to a complete loss of binding sensitivity to the inhibitory effect of 120 mM NaCl + 50 μm Gpp(NH)p compared to the high sensitivity of DPDYN. This may therefore suggest that the N,N-diallyl-DPDYN analogues are endowed with opioid antagonist properties. 4 No agonist activity of the analogues was observed in guinea-pig myenteric plexus and rabbit vas deferens organ preparations. In contrast, both of the diallyl-substituted peptides displayed similar antagonist properties against the κ-agonist DPDYN in both preparations. In the guinea-pig ileum, the affinities of the antagonist peptides against the μ-agonist Tyr-D-Ala-Gly-MePhe-NH(CH2)2OH(DAGOL) were approximately half that observed against DPDYN. 5 These results show that N,N-diallyl-tyrosyl substitution leads to analogues of DPDYN which act in vitro as pure opioid antagonists and exhibit a reasonable affinity at, but a weak selectivity for, the κ-opioid receptors.