The role of amino-terminal sequence of beta-endorphin and dynorphin in the determination of opiate receptor type selectivity.
Previous studies have shown that morphiceptin is a highly selective mu-receptor agonist. Recently we have obtained a more potent and stable analog, Tyr-Pro-NMePhe-D-Pro-NH2 (PL017). This peptide retains mu-receptor selectivity. beta-Endorphin is known to be a potent but non-selective opioid peptide for mu-, delta- and benzomorphan binding sites. Dynorphin is a putative kappa-agonist with significant affinity to mu-, delta- and benzomorphan binding sites in rat brain membranes. To understand the structural requirement for receptor type selectivity the enkephalin sequence of beta-endorphin and dynorphin was replaced by that of morphiceptin analog. Replacing the Met-enkephalin sequence of beta h-endorphin by PL017 yields a peptide highly selective for mu-binding sites. Substituting the Leu-enkephalin sequence of dynorphin-17 produces a peptide [PL017-dynorphin(6-17)] that retains high affinities for mu- and kappa-binding sites and has very low affinities for delta- and benzomorphan binding sites. These results suggest that a morphiceptin sequence at the amino-terminus of large opioid peptides can dictate mu-receptor selectivity. An enkephalin sequence at the amino-terminus of large opioid peptides seems to be required to retain high affinity for delta- and benzomorphan binding sites. The high affinity of PL017-dynorphin(6-17) for kappa-binding sites but not for benzomorphan binding sites suggests that benzomorphan sites of rat brain are not kappa-sites.
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004399:Dynorphins; D004723:Endorphins / Q000378:metabolism*; D009294:Narcotics / Q000494:pharmacology; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D013329:Structure-Activity Relationship; D001615:beta-Endorphin
D004723:Endorphins; D009294:Narcotics; D011957:Receptors, Opioid; D001615:beta-Endorphin; D004399:Dynorphins