title: Synthesis and evaluation of melphalan-containing N,N-dialkylenkephalin analogues as irreversible antagonists of the delta opioid receptor.
abstract: N,N-Dialkylated leucine enkephalin analogues containing melphalan (Mel) 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 two of the eight compounds showed antagonist activity at 1 microM against [D-Ala2,D-Leu5]enkephalin (DADLE) 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 higher concentrations (10 microM) the two active Mel4 analogues, (benzyl)2Tyr-Gly-Gly-Mel-Leu (2a) and (allyl)2Tyr-Aib-Aib-Mel-Leu (3a), both showed weak irreversible antagonism at the delta receptor. Compound 2a was a selective irreversible delta opioid antagonist while 3a was an irreversible antagonist at both the mu and delta opioid receptors.
mesh_terms: D000478:Alkylation; D000818:Animals; D003496:Cyclazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D016314:Ethylketocyclazocine; D006168:Guinea Pigs; D008558:Melphalan; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D013329:Structure-Activity Relationship
chemical_list: D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D016314:Ethylketocyclazocine; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine; D003496:Cyclazocine; D008558:Melphalan