title: Design, synthesis, and biological evaluation of (3R)-1,2,3,4-tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide (JDTic) analogues: in vitro pharmacology and ADME profile.
abstract: JDTic analogues 4-15 which have the hydroxyl groups replaced with other groups were synthesized and their in vitro efficacy at the μ, δ, and κ opioid receptors determined and compared to JDTic using [(35)S]GTPγS assays. Compounds 4, 5, 6, 13, 14, and 15 had Ke = 0.024, 0.01, 0.039, 0.02, 0.11, and 0.041 nM compared to the Ke = 0.02 nM for JDTic at the κ receptor and were highly selective for the κ receptor relative to the μ and δ opioid receptors. Unexpectedly, replacement of the 3-hydroxyl substituent of the 4-(3-hydroxyphenyl) group of JDTic with a H, F, or Cl substituent leads to potent and selective KOR antagonists. In vitro studies to determine various ADME properties combined with calculated TPSA, clogP, and logBB values suggests that the potent and selective κ opioid receptors 4, 5, 13, and 14 deserve consideration for further development toward potential drugs for CNS disorders.
authors.affiliation: Research Triangle Institute , 3040 Cornwallis Road, P.O. Box 12194, Research Triangle Park, North Carolina 27709-6679, United States.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Kormos
authors.forename: Moses G
authors.initials: MG
authors.lastname: Gichinga
authors.forename: Rangan
authors.initials: R
authors.lastname: Maitra
authors.forename: Scott P
authors.initials: SP
authors.lastname: Runyon
authors.forename: James B
authors.initials: JB
authors.lastname: Thomas
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Brieaddy
authors.forename: S Wayne
authors.initials: SW
authors.lastname: Mascarella
authors.forename: Hernán A
authors.initials: HA
authors.lastname: Navarro
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
mesh_terms: D001667:Binding, Competitive; D015195:Drug Design; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000378:metabolism / 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; D017473:Receptors, Opioid, kappa; D044005:Tetrahydroisoquinolines; D016244:Guanosine 5'-O-(3-Thiotriphosphate)