title: Synthesis and pharmacology of halogenated δ-opioid-selective [d-Ala(2)]deltorphin II peptide analogues.
abstract: Deltorphins are naturally occurring peptides produced by the skin of the giant monkey frog (Phyllomedusa bicolor). They are δ-opioid receptor-selective agonists. Herein, we report the design and synthesis of a peptide, Tyr-d-Ala-(pI)Phe-Glu-Ile-Ile-Gly-NH2 3 (GATE3-8), based on the [d-Ala(2)]deltorphin II template, which is δ-selective in in vitro radioligand binding assays over the μ- and κ-opioid receptors. It is a full agonist in [(35)S]GTPγS functional assays and analgesic when administered supraspinally to mice. Analgesia of 3 (GATE3-8) is blocked by the selective δ receptor antagonist naltrindole, indicating that the analgesic action of 3 is mediated by the δ-opioid receptor. We have established a radioligand in which (125)I is incorporated into 3 (GATE3-8). The radioligand has a KD of 0.1 nM in Chinese hamster ovary (CHO) cells expressing the δ receptor. Additionally, a series of peptides based on 3 (GATE3-8) was synthesized by incorporating various halogens in the para position on the aromatic ring of Phe(3). The peptides were characterized for binding affinity at the μ-, δ-, and κ-opioid receptors, which showed a linear correlation between binding affinity and the size of the halogen substituent. These peptides may be interesting tools for probing δ-opioid receptor pharmacology.
authors.affiliation: †Department of Chemistry, Wingate University, PO Box 159, Wingate, North Carolina 28174, United States.
authors.forename: Robyn
authors.initials: R
authors.lastname: Pescatore
authors.affiliation: ‡Department of Neuroscience, Weil Cornell Medical College, 1300 York Avenue, New York, New York 10065, United States.|§Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Gina F
authors.initials: GF
authors.lastname: Marrone
authors.affiliation: †Department of Chemistry, Wingate University, PO Box 159, Wingate, North Carolina 28174, United States.
authors.forename: Seth
authors.initials: S
authors.lastname: Sedberry
authors.affiliation: †Department of Chemistry, Wingate University, PO Box 159, Wingate, North Carolina 28174, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Vinton
authors.affiliation: §Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Netanel
authors.initials: N
authors.lastname: Finkelstein
authors.affiliation: §Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Yitzchak E
authors.initials: YE
authors.lastname: Katlowitz
authors.affiliation: ‡Department of Neuroscience, Weil Cornell Medical College, 1300 York Avenue, New York, New York 10065, United States.|§Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Gavril W
authors.initials: GW
authors.lastname: Pasternak
authors.affiliation: †Department of Chemistry, Wingate University, PO Box 159, Wingate, North Carolina 28174, United States.
authors.forename: Krista R
authors.initials: KR
authors.lastname: Wilson
authors.affiliation: §Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Susruta
authors.initials: S
authors.lastname: Majumdar
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054879:Halogenation; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D009842:Oligopeptides; D010455:Peptides; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C060209:deltorphin II, Ala(2)-
keywords: Deltorphin; delta opioid receptor; radioiodination; sandmeyer
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