title: Development and in vitro characterization of a novel bifunctional μ-agonist/δ-antagonist opioid tetrapeptide.
abstract: The development of tolerance to and dependence on opioid analgesics greatly reduces their long-term usefulness. Previous studies have demonstrated that co-administration of a μ-opioid receptor (MOR) agonist and δ-opioid receptor (DOR) antagonist can decrease MOR agonist-induced tolerance and dependence development after chronic exposure. Clinically, a single ligand displaying multiple efficacies (e.g., MOR agonism concurrently with DOR antagonism) would be of increased value over two drugs administered simultaneously. Guided by modeling of receptor-ligand complexes we have developed a series of potent non-selective opioid tetrapeptides that have differing efficacy at MOR and DOR. In particular, our lead peptide (KSK-103) binds with equal affinity to MOR and DOR but acts as a MOR agonist with similar efficacy but greater potency than morphine and a DOR antagonist in cellular assays measuring both G protein stimulation and adenylyl cyclase inhibition.
authors.affiliation: Medical School and College of Pharmacy, Department of Pharmacology, University of Michigan, Ann Arbor 48109, USA.
authors.forename: Lauren C
authors.initials: LC
authors.lastname: Purington
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Sobczyk-Kojiro
authors.forename: Irina D
authors.initials: ID
authors.lastname: Pogozheva
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
authors.forename: Henry I
authors.initials: HI
authors.lastname: Mosberg
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004361:Drug Tolerance; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000701:Analgesics, Opioid; D003432:Cross-Linking Reagents; C571159:KSK-103; D009292:Narcotic Antagonists; D009842:Oligopeptides; D010456:Peptides, Cyclic; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate)