title: Melphalan potently substitutes the N-terminal Tyr of D-Ala2-Leu5-enkephalin methyl ester.
abstract: In search of an affinity label of the opioid receptor, the nitrogen mustard melphalan, Mel, was built into the peptide chain of D-Ala2-Leu5-enkephalin (DALE) methyl ester in different positions. We report now that in contrast to the previous observations that an intact Tyr in position 1 is essential for opioid activity [(1980) Annu. Rev. Pharmacol. Toxicol. 20, 81-110], substitution of Tyr by Mel did not result in a loss of the binding affinity. Mel1, Leu5-enkephalin-OMe competed for the binding sites of [3H]naloxone as potently as DALE did; IC50 values for both compounds were 50 nM. Mel substitution has led to one order potency decrease in binding to the delta-sites. 0.5-1 microM of the compound irreversibly inactivates 50% of the binding sites of [3H]naloxone, and 5-10 microM of that of [3H]DALE. These results shed new light on the structural requirements established for opioid peptides. In addition, the new derivative can be used as an affinity label of the opioid receptor.
authors.forename: M
authors.initials: M
authors.lastname: Szücs
authors.forename: K
authors.initials: K
authors.lastname: Di Gleria
authors.forename: K
authors.initials: K
authors.lastname: Medzihradszky
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine / Q000031:analogs & derivatives*; D007700:Kinetics; D008558:Melphalan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D009270:Naloxone / Q000378:metabolism; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*
chemical_list: D011957:Receptors, Opioid; D009270:Naloxone; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; C040240:enkephalin-Leu, Ala(2)-melphalan methyl ester-; D008558:Melphalan