title: Potency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif.
abstract: Optimization of the sulfonamide-based kappa opioid receptor (KOR) antagonist probe molecule ML140 through constraint of the sulfonamide nitrogen within a tetrahydroisoquinoline moiety afforded a marked increase in potency. This strategy, when combined with additional structure-activity relationship exploration, has led to a compound only six-fold less potent than norBNI, a widely utilized KOR antagonist tool compound, but significantly more synthetically accessible. The new optimized probe is suitably potent for use as an in vivo tool to investigate the therapeutic potential of KOR antagonists.
authors.affiliation: University of Kansas Specialized Chemistry Center, 2034 Becker Drive, Lawrence, KS 66047-3761, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Frankowski
authors.affiliation: University of Kansas Specialized Chemistry Center, 2034 Becker Drive, Lawrence, KS 66047-3761, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Slauson
authors.affiliation: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, 130 Scripps Way, #2A2, Jupiter, FL 33458, USA.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Lovell
authors.affiliation: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, 130 Scripps Way, #2A2, Jupiter, FL 33458, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Phillips
authors.affiliation: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, 130 Scripps Way, #2A2, Jupiter, FL 33458, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Streicher
authors.affiliation: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, 130 Scripps Way, #2A2, Jupiter, FL 33458, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: University of Kansas Specialized Chemistry Center, 2034 Becker Drive, Lawrence, KS 66047-3761, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Whipple
authors.affiliation: University of Kansas Specialized Chemistry Center, 2034 Becker Drive, Lawrence, KS 66047-3761, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Schoenen
authors.affiliation: University of Kansas Specialized Chemistry Center, 2034 Becker Drive, Lawrence, KS 66047-3761, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
authors.affiliation: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, 130 Scripps Way, #2A2, Jupiter, FL 33458, USA. Electronic address: lbohn@scripps.edu.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Bohn
authors.affiliation: University of Kansas Specialized Chemistry Center, 2034 Becker Drive, Lawrence, KS 66047-3761, USA. Electronic address: jaube@ku.edu.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D060326:Chemistry Techniques, Synthetic; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical / Q000379:methods; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D009271:Naltrexone / Q000031:analogs & derivatives / Q000737:chemistry; D009292:Narcotic Antagonists / Q000737:chemistry / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000235:genetics; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines / Q000737:chemistry; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D001549:Benzamides; C000605945:ML140 compound; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D013449:Sulfonamides; D044005:Tetrahydroisoquinolines; D000071557:beta-Arrestins; C051844:norbinaltorphimine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009271:Naltrexone
keywords: Antagonist; Kappa opioid receptor; Molecular constraint; Potency enhancement; Tetrahydroisoquinoline