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Type: Journal article
Title: Conopeptide-derived κ-opioid agonists (conorphins): potent, selective, and metabolic stable dynorphin A mimetics with antinociceptive properties
Other Titles: Conopeptide-derived kappa-opioid agonists (conorphins): potent, selective, and metabolic stable dynorphin A mimetics with antinociceptive properties
Author: Brust, A.
Croker, D.
Colless, B.
Ragnarsson, L.
Andersson, Å.
Jain, K.
Garcia-Caraballo, S.
Castro, J.
Brierley, S.
Alewood, P.
Lewis, R.
Citation: Journal of Medicinal Chemistry, 2016; 59(6):2381-2395
Publisher: American Chemical Society
Issue Date: 2016
ISSN: 0022-2623
Statement of
Andreas Brust, Daniel E. Croker, Barbara Colless, Lotten Ragnarsson, Åsa Andersson, Kapil Jain, Sonia Garcia-Caraballo, Joel Castro, Stuart M Brierley, Paul F. Alewood and Richard J. Lewis
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.
Keywords: Neurons, Afferent; CHO Cells; Animals; Mice, Inbred C57BL; Cricetulus; Mice; Rats; Rats, Wistar; Hypersensitivity; Abdominal Pain; Dynorphins; Peptide Library; Receptors, Opioid, kappa; Cyclic AMP; Analgesics; Structure-Activity Relationship; Cricetinae; Male; Conus Snail; High-Throughput Screening Assays; Molecular Docking Simulation
Rights: Copyright © 2016 American Chemical Society
RMID: 0030043867
DOI: 10.1021/acs.jmedchem.5b00911
Grant ID:
Appears in Collections:Medicine publications

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