| Abstract
| - The peptide [Pro3]Dyn A(1−11)-NH22 exhibits high affinity (Ki = 2.4 nM) and over 2000-foldselectivity for the κ opioid receptor. Stepwise removal of the C-terminal residues from thisligand demonstrated that its positively charged Arg residues, particularly Arg6 and Arg7, werecrucial for binding to the κ receptor. Analogues shorter than seven amino acids lacked significantaffinity for opioid receptors. Comparison with a series of truncated analogues of Dyn A showedthat the relative losses in binding potency differed only slightly between the two series. Theneutral residues Ile8 and Pro10 could be removed without significant loss in affinity for the κreceptor. Their replacement, in the Pro3 analogue, with additional Arg residues led to analogueswith improved κ affinity (e.g., [Pro3,Arg8]Dyn A(1−11)-NH220: Ki(κ) = 0.44 nM). This type ofmodification did not compromise the high κ selectivity of the Pro3 analogues. These findingssupport the view that a negatively charged domain in the putative second extracellular loop ofthe κ receptor selectively recognizes residues 6−11 of dynorphin through electrostaticinteractions. As with parent compound 2, analogue 20 and related compounds displayed κantagonist properties.
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