title: Melphalan-containing N,N-dialkylenkephalin analogs as potential irreversible antagonists of the delta opioid receptor.
abstract: N,N-Dialkylated leucine enkephalin analogs containing melphalan in place of Phe4 were synthesized as potentially irreversible antagonists of the delta opioid receptor. These compounds, along with the corresponding Phe4 peptides, were tested for both agonist and antagonist activity in the GPI and MVD smooth muscle preparations. All but one of the compounds showed antagonist activity at 10(-6) M against [D-Ala2,D-Leu5] enkephalin in the MVD when tested under reversible conditions; in all cases the Mel4 peptide had lower activity against DADLE than did the corresponding Phe4 peptide. At high concentrations (10(-5) M) the active Mel4 analogs, (benzyl)2Tyr-Gly-Gly-Mel-Leu and (allyl)2Tyr-Aib-Aib-Mel-Leu, both showed weak irreversible antagonism at the delta receptor.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
authors.forename: J A
authors.initials: JA
authors.lastname: Lovett
authors.forename: P S
authors.initials: PS
authors.lastname: Portoghese
mesh_terms: D000818:Animals; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D004745:Enkephalins / Q000138:chemical synthesis / Q000494:pharmacology*; D008558:Melphalan / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011957:Receptors, Opioid / Q000187:drug effects*; D017465:Receptors, Opioid, delta; D013329:Structure-Activity Relationship
chemical_list: D004745:Enkephalins; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine; D008558:Melphalan