Two series of nociceptin (NC)-related peptides with or without replacement of the N-terminal Phe by Tyr have been investigated in an attempt to obtain compounds that interact with the NC receptor ...(ORL1) and classic opioid receptors. When tested for their ability to displace 3HNCNH2 (3Hnociceptin amide; ORL1 sites) or the selective opioid receptor ligands 3HDAMGO (mu), 3Hdeltorphin II (delta) and 3HU69593 (kappa) from their respective binding sites in guinea-pig brain membranes, Tyr1NCNH2 and Tyr1NC(1-13)NH2 showed high affinities (Ki 2nM and 5 nM, respectively) for ORL1 and approximately tenfold lower potency for mu (32nM and 44nM) and kappa sites (42 nM and 48 nM). They also interacted, but with low potency (Ki 410 nM and 310 nM) with delta sites. Shorter fragments as Tyr1NC(1-9)NH2 and Tyr1NC(1-5)NH2 were found to be inactive on ORL1, delta and kappa sites, and extremely weak (Ki 2224 nM and 4228 nM, respectively) on mu. Results of bioassays performed on the guinea-pig ileum (ORL1 and mu receptors), mouse vas deferens (ORL1 and delta receptors), and rabbit vas deferens (kappa receptor) confirmed (at least partially) the data of the binding by showing that Tyr1NC analogs interact with functional ORL1 as well as with classic opioid receptors. Tyr1NCNH2 and Tyr1NC(1-13)NH2 behaved as mixed ORL1/opioid receptor agonists showing similar affinities as the control NC sequence while Tyr1NC(1-9)NH2 and Tyr1NC(1-5)NH2 were inactive on ORL1 receptors but maintained some activities on opioid receptors: their effects were prevented by naloxone. The results of this study indicate that the replacement of Phe1 by Tyr in NC leads to compounds which bind both the ORL1 and mu/kappa receptors and may represent new promising agents for use in peripheral organs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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