title: Identification of the first trans-(3R,4R)- dimethyl-4-(3-hydroxyphenyl)piperidine derivative to possess highly potent and selective opioid kappa receptor antagonist activity.
abstract: A structurally novel opioid kappa receptor selective ligand has been identified. This compound, (3R)-7-hydroxy-N-((1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 10) demonstrated high affinity for the kappa receptor in the binding assay (kappa K(i) = 0.3 nM) and highly potent and selective kappa antagonism in the [(35)S]GTP-gamma-S assay using cloned opioid receptors (kappa K(i) = 0.006 nM, mu/kappa ratio = 570, delta/kappa ratio > 16600).
authors.affiliation: Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Thomas
authors.forename: R N
authors.initials: RN
authors.lastname: Atkinson
authors.forename: R B
authors.initials: RB
authors.lastname: Rothman
authors.forename: S E
authors.initials: SE
authors.lastname: Fix
authors.forename: S W
authors.initials: SW
authors.lastname: Mascarella
authors.forename: N A
authors.initials: NA
authors.lastname: Vinson
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.forename: C M
authors.initials: CM
authors.lastname: Dersch
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: B E
authors.initials: BE
authors.lastname: Cantrell
authors.forename: D M
authors.initials: DM
authors.lastname: Zimmerman
authors.forename: F I
authors.initials: FI
authors.lastname: Carroll
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D003001:Cloning, Molecular; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines
chemical_list: C433814:7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide; D007546:Isoquinolines; D009292:Narcotic Antagonists; D010880:Piperidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines