title: Conopeptide-Derived κ-Opioid Agonists (Conorphins): Potent, Selective, and Metabolic Stable Dynorphin A Mimetics with Antinociceptive Properties.
abstract: Opioid receptor screening of a conopeptide library led to a novel selective κ-opioid agonist peptide (conorphin T). Intensive medicinal chemistry, guided by potency, selectivity, and stability assays generated a pharmacophore model supporting rational design of highly potent and selective κ-opioid receptor (KOR) agonists (conorphins) with exceptional plasma stability. Conorphins are defined by a hydrophobic benzoprolyl moiety, a double arginine sequence, a spacer amino acid followed by a hydrophobic residue and a C-terminal vicinal disulfide moiety. The pharmacophore model was supported by computational docking studies, revealing receptor-ligand interactions similar to KOR agonist dynorphin A (1-8). A conorphin agonist inhibited colonic nociceptors in a mouse tissue model of chronic visceral hypersensitivity, suggesting the potential of KOR agonists for the treatment of chronic abdominal pain. This new conorphine KOR agonist class and pharmacophore model provide opportunities for future rational drug development and probes for exploring the role of the κ-opioid receptor.
authors: Xenome Limited , Brisbane, Queensland 4068, Australia.|Institute for Molecular Biosciences, The University of Queensland , Brisbane, Queensland, 4072, Australia.
authors: Andreas
authors: A
authors: Brust
authors: Xenome Limited , Brisbane, Queensland 4068, Australia.|Institute for Molecular Biosciences, The University of Queensland , Brisbane, Queensland, 4072, Australia.
authors: Daniel E
authors: DE
authors: Croker
authors: Xenome Limited , Brisbane, Queensland 4068, Australia.|Institute for Molecular Biosciences, The University of Queensland , Brisbane, Queensland, 4072, Australia.
authors: Barbara
authors: B
authors: Colless
authors: Xenome Limited , Brisbane, Queensland 4068, Australia.|Institute for Molecular Biosciences, The University of Queensland , Brisbane, Queensland, 4072, Australia.
authors: Lotten
authors: L
authors: Ragnarsson
authors: Xenome Limited , Brisbane, Queensland 4068, Australia.|Institute for Molecular Biosciences, The University of Queensland , Brisbane, Queensland, 4072, Australia.
authors: Åsa
authors: Å
authors: Andersson
authors: Institute for Molecular Biosciences, The University of Queensland , Brisbane, Queensland, 4072, Australia.
authors: Kapil
authors: K
authors: Jain
authors: Visceral Pain Group, Centre for Nutrition and Gastrointestinal Disease, Discipline of Medicine, The University of Adelaide, South Australian Health and Medical Research Institute, SAHMRI , Adelaide, SA 5000, Australia.
authors: Sonia
authors: S
authors: Garcia-Caraballo
authors: Visceral Pain Group, Centre for Nutrition and Gastrointestinal Disease, Discipline of Medicine, The University of Adelaide, South Australian Health and Medical Research Institute, SAHMRI , Adelaide, SA 5000, Australia.
authors: Joel
authors: J
authors: Castro
authors: Visceral Pain Group, Centre for Nutrition and Gastrointestinal Disease, Discipline of Medicine, The University of Adelaide, South Australian Health and Medical Research Institute, SAHMRI , Adelaide, SA 5000, Australia.
authors: Stuart M
authors: SM
authors: Brierley
authors: Institute for Molecular Biosciences, The University of Queensland , Brisbane, Queensland, 4072, Australia.
authors: Paul F
authors: PF
authors: Alewood
authors: Xenome Limited , Brisbane, Queensland 4068, Australia.|Institute for Molecular Biosciences, The University of Queensland , Brisbane, Queensland, 4072, Australia.
authors: Richard J
authors: RJ
authors: Lewis
mesh_terms: D015746:Abdominal Pain / Q000188:drug therapy; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D052078:Conus Snail / Q000737:chemistry*; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D004399:Dynorphins / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006967:Hypersensitivity / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D009475:Neurons, Afferent / Q000187:drug effects; D019151:Peptide Library; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D019151:Peptide Library; D017473:Receptors, Opioid, kappa; D004399:Dynorphins; D000242:Cyclic AMP