title: N,N-diallyl-tyrosyl substitution confers antagonist properties on the kappa-selective opioid peptide [D-Pro10]dynorphin A(1-11).
abstract: 1. In the search for kappa-opioid antagonists, we have designed two N,N-diallyl substituted analogues of the kappa-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 (mu, delta, kappa) of opioid binding sites, (ii) their binding sensitivity to Na+ ions (120 mM NaCl) and guanine nucleotide (50 microM Gpp(NH)p) at mu- and kappa-binding sites and (iii) their biological activity in two pharmacological bioassays specific for mu- and kappa-(guinea-pig ileum) and kappa-(rabbit vas deferens) opioid receptors. 2. Steric hindrance resulting from incorporation of two bulky allyl groups at the tyrosal nitrogen atom greatly altered the binding properties of DPDYN. A dramatic fall in apparent affinity for the three types (mu, delta, kappa) of site as well as selectivity for kappa-sites was observed for the two N,N-diallyl-substituted peptide analogues. 3. At kappa-sites of guinea-pig cerebellum and mu-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 microM 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 kappa-agonist DPDYN in both preparations. In the guinea-pig ileum, the affinities of the antagonist peptides against the mu-agonist Tyr-D-Ala-Gly-MePhe- NH(CH2)20H(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 K-opioid receptors.
authors.affiliation: Laboratoire de Pharmacologie et de Toxicologie Fondamentales, Centre National de la Recherche Scientifique, Toulouse, France.
authors.forename: J E
authors.initials: JE
authors.lastname: Gairin
authors.forename: H
authors.initials: H
authors.lastname: Mazarguil
authors.forename: P
authors.initials: P
authors.lastname: Alvinerie
authors.forename: C
authors.initials: C
authors.lastname: Botanch
authors.forename: J
authors.initials: J
authors.lastname: Cros
authors.forename: J C
authors.initials: JC
authors.lastname: Meunier
mesh_terms: D000498:Allyl Compounds / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004399:Dynorphins / Q000378:metabolism / Q000494:pharmacology*; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D012964:Sodium / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000498:Allyl Compounds; D010446:Peptide Fragments; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D006165:Guanylyl Imidodiphosphate; D014443:Tyrosine; D004399:Dynorphins; C044619:dynorphin (1-11), Pro(10)-; D012964:Sodium