title: Structure-activity relationship studies of functionally selective kappa opioid receptor agonists that modulate ERK 1/2 phosphorylation while preserving G protein over βarrestin2 signaling bias.
abstract: Kappa opioid receptor (KOR) modulation is a promising target for drug discovery efforts due to KOR involvement in pain, depression, and addiction behaviors. We recently reported a new class of triazole KOR agonists that displays significant bias toward G protein signaling over βarrestin2 recruitment; interestingly, these compounds also induce less activation of ERK1/2 map kinases than the balanced agonist, U69,593. We have identified structure-activity relationships around the triazole scaffold that allows for decreasing the bias for G protein signaling over ERK1/2 activation while maintaining the bias for G protein signaling over βarrestin2 recruitment. The development of novel compounds, with different downstream signaling outcomes, independent of G protein/βarrestin2 bias, provides a more diverse pharmacological toolset for use in defining complex KOR signaling and elucidating the significance of KOR-mediated signaling.
authors.affiliation: †Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Lovell
authors.affiliation: ‡Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Frankowski
authors.affiliation: †Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Stahl
authors.affiliation: ‡Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Slauson
authors.affiliation: ‡Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States.
authors.forename: Euna
authors.initials: E
authors.lastname: Yoo
authors.affiliation: ‡Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
authors.affiliation: ‡Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
authors.affiliation: †Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Bohn
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D044482:Benzeneacetamides / Q000494:pharmacology; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D000071557:beta-Arrestins
chemical_list: D000701:Analgesics, Opioid; D019390:Arrestins; D044482:Benzeneacetamides; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D011994:Recombinant Proteins; D000071557:beta-Arrestins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019204:GTP-Binding Proteins; C045444:U 69593
keywords: Functional selectivity; G protein coupling; GPCR; MAP kinase; arrestin; biased agonism