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N,N-diallyl-tyrosyl substitution confers antagonist properties on the kappa-selective opioid peptide [D-Pro10]dynorphin A(1-11). 1988

J E Gairin, and H Mazarguil, and P Alvinerie, and C Botanch, and J Cros, and J C Meunier
Laboratoire de Pharmacologie et de Toxicologie Fondamentales, Centre National de la Recherche Scientifique, Toulouse, France.

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.

UI MeSH Term Description Entries
D008297 Male Males
D010446 Peptide Fragments Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques. Peptide Fragment,Fragment, Peptide,Fragments, Peptide
D011817 Rabbits A burrowing plant-eating mammal with hind limbs that are longer than its fore limbs. It belongs to the family Leporidae of the order Lagomorpha, and in contrast to hares, possesses 22 instead of 24 pairs of chromosomes. Belgian Hare,New Zealand Rabbit,New Zealand Rabbits,New Zealand White Rabbit,Rabbit,Rabbit, Domestic,Chinchilla Rabbits,NZW Rabbits,New Zealand White Rabbits,Oryctolagus cuniculus,Chinchilla Rabbit,Domestic Rabbit,Domestic Rabbits,Hare, Belgian,NZW Rabbit,Rabbit, Chinchilla,Rabbit, NZW,Rabbit, New Zealand,Rabbits, Chinchilla,Rabbits, Domestic,Rabbits, NZW,Rabbits, New Zealand,Zealand Rabbit, New,Zealand Rabbits, New,cuniculus, Oryctolagus
D011957 Receptors, Opioid Cell membrane proteins that bind opioids and trigger intracellular changes which influence the behavior of cells. The endogenous ligands for opioid receptors in mammals include three families of peptides, the enkephalins, endorphins, and dynorphins. The receptor classes include mu, delta, and kappa receptors. Sigma receptors bind several psychoactive substances, including certain opioids, but their endogenous ligands are not known. Endorphin Receptors,Enkephalin Receptors,Narcotic Receptors,Opioid Receptors,Receptors, Endorphin,Receptors, Enkephalin,Receptors, Narcotic,Receptors, Opiate,Endorphin Receptor,Enkephalin Receptor,Normorphine Receptors,Opiate Receptor,Opiate Receptors,Opioid Receptor,Receptors, Normorphine,Receptors, beta-Endorphin,beta-Endorphin Receptor,Receptor, Endorphin,Receptor, Enkephalin,Receptor, Opiate,Receptor, Opioid,Receptor, beta-Endorphin,Receptors, beta Endorphin,beta Endorphin Receptor,beta-Endorphin Receptors
D004399 Dynorphins A class of opioid peptides including dynorphin A, dynorphin B, and smaller fragments of these peptides. Dynorphins prefer kappa-opioid receptors (RECEPTORS, OPIOID, KAPPA) and have been shown to play a role as central nervous system transmitters. Dynorphin,Dynorphin (1-17),Dynorphin A,Dynorphin A (1-17)
D006165 Guanylyl Imidodiphosphate A non-hydrolyzable analog of GTP, in which the oxygen atom bridging the beta to the gamma phosphate is replaced by a nitrogen atom. It binds tightly to G-protein in the presence of Mg2+. The nucleotide is a potent stimulator of ADENYLYL CYCLASES. GMP-PNP,GMP-P(NH)P,Gpp(NH)p,Guanosine 5'-(Beta,Gamma-Imido)Triphosphate,Guanyl-5'-Imidodiphosphate,P(NH)PPG,Guanyl 5' Imidodiphosphate,Imidodiphosphate, Guanylyl
D006168 Guinea Pigs A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. Cavia,Cavia porcellus,Guinea Pig,Pig, Guinea,Pigs, Guinea
D000498 Allyl Compounds Alkenes with the general formula H2C Compounds, Allyl
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012964 Sodium A member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. Sodium Ion Level,Sodium-23,Ion Level, Sodium,Level, Sodium Ion,Sodium 23

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