title: Pharmacological characterization of the dermorphin analog [Dmt(1)]DALDA, a highly potent and selective mu-opioid peptide.
abstract: The dermorphin-derived peptide [Dmt(1)]DALDA (H-Dmt-D-Arg-Phe-Lys-NH(2)), labels mu-opioid receptors with high affinity and selectivity in receptor binding assays. In mouse, radiant heat tail-flick assay [Dmt(1)]DALDA produced profound spinal and supraspinal analgesia, being approximately 5000- and 100-fold more potent than morphine on a molar basis, respectively. When administered systemically, [Dmt(1)]DALDA was over 200-fold more potent than morphine. Pharmacologically, [Dmt(1)]DALDA was distinct from morphine. [Dmt(1)]DALDA displayed no cross-tolerance to morphine in the model used and it retained supraspinal analgesic activity in morphine-insensitive CXBK mice. Supraspinally, it also differed from morphine in its lack of sensitivity towards naloxonazine. Finally, in antisense mapping studies, [Dmt(1)]DALDA was insensitive to MOR-1 exon probes that reduced morphine analgesia, implying a distinct receptor mechanism of action. Thus, [Dmt(1)]DALDA is an interesting and extraordinarily potent, systemically active peptide analgesic, raising the possibility of novel approaches in the design of clinically useful drugs.
authors.affiliation: Department of Molecular Neuropharmacology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Neilan
authors.forename: T M
authors.initials: TM
authors.lastname: Nguyen
authors.forename: P W
authors.initials: PW
authors.lastname: Schiller
authors.forename: G W
authors.initials: GW
authors.lastname: Pasternak
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D004361:Drug Tolerance; D006801:Humans; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018847:Opioid Peptides; D010147:Pain Measurement; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013997:Time Factors
chemical_list: C107547:3-methoxynaltrexone; D000700:Analgesics; D009292:Narcotic Antagonists; D020319:Oligodeoxyribonucleotides, Antisense; D009842:Oligopeptides; D018847:Opioid Peptides; D017450:Receptors, Opioid, mu; C063076:tyrosyl-arginyl-phenylalanyl-lysinamide; C030058:dermorphin; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; C024524:beta-funaltrexamine; D009020:Morphine; C055382:naltrindole