title: Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of replacement of the 3-hydroxyphenyl group with pyridine or thiophene bioisosteres.
abstract: The potent and selective KOR antagonist JDTic was derived from the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of pure opioid antagonists. In previous studies we reported that compounds that did not have a hydroxyl on the 3-hydroxyphenyl group and did not have methyl groups at the 3- and 4-position of the piperidine ring were still potent and selective KOR antagonists. In this study we report JDTic analogs 2, 3a-b, 4a-b, and 5, where the 3-hydroxyphenyl ring has been replaced by a 2-, 3-, or 4-pyridyl or 3-thienyl group and do not have the 3-methyl or 3,4-dimethyl groups, remain potent and selective KOR antagonists. Of these, (3R)-7-hydroxy-N-(1S)-2-methyl-[4-methyl-4-pyridine-3-yl-carboxamide (3b) had the best overall binding potency and selectivity in a [(35)S]GTPγS functional assay, with a Ke=0.18nM at the KOR and 273- and 16,700-fold selectivity for the KOR relative to the MOR and DOR, respectively. Calculated physiochemical properties for 3b suggest that it will cross the blood-brain barrier.
authors.affiliation: Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Kormos
authors.affiliation: Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
authors.forename: Moses G
authors.initials: MG
authors.lastname: Gichinga
authors.affiliation: Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Runyon
authors.affiliation: Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
authors.forename: James B
authors.initials: JB
authors.lastname: Thomas
authors.affiliation: Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
authors.forename: S Wayne
authors.initials: SW
authors.lastname: Mascarella
authors.affiliation: Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Decker
authors.affiliation: Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
authors.forename: Hernán A
authors.initials: HA
authors.lastname: Navarro
authors.affiliation: Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States. Electronic address: fic@rti.org.
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
mesh_terms: D001812:Blood-Brain Barrier; D015195:Drug Design; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013057:Spectrum Analysis / Q000379:methods; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
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; D010880:Piperidines; D011725:Pyridines; D044005:Tetrahydroisoquinolines; D013876:Thiophenes
keywords: ADME properties; JDTic; Kappa antagonist; Opioids