title: Pharmacodynamic Relationships between Duration of Action of JDTic-like Kappa-Opioid Receptor Antagonists and Their Brain and Plasma Pharmacokinetics in Rats.
abstract: JDTic is a potent and selective κ-opioid receptor (KOR) antagonist that reverses U50,488-induced diuresis in rats. It partitions into brain with a duration of action lasting for weeks. In a search for KOR antagonists that do not accumulate in the brain, we compared single doses of five methylated JDTic analogs (RTI-97, -194, -212, -240, and -241) for reversal of U50,488 diuresis and pharmacokinetic (PK) properties. All six compounds showed potent and selective KOR antagonism in a [35S]GTPγS binding assay. Plasma half-lives ranged from 24 to 41 h and brain half-lives from 24 to 76 h. JDTic and RTI-194 showed increasing brain to plasma ratios over time, indicating increasing partitioning into brain and a longer duration of action for reversal of diuresis than did RTI-97. RTI-240 did not show significant brain accumulation. RTI-212 showed no substantive difference between brain and plasma levels and was inactive against diuresis. RTI-241, with a lower brain to plasma ratio than JDTic and RTI-194, formed JDTic as a metabolite, which still reduced diuresis after 9 weeks. The fact that the duration of action was correlated with the brain to blood plasma ratios and area under the concentration-time curves suggests that PK properties could help to predict safety and acceptable duration of action for KOR antagonists.
authors.affiliation: University of Arkansas for Medical Sciences , College of Medicine, Department of Pharmacology and Toxicology, Little Rock, Arkansas 72205, United States.
authors.forename: S Michael
authors.initials: SM
authors.lastname: Owens
authors.affiliation: Howard Associates, LLC , 3040 East Cornwallis Road, P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Pollard
authors.affiliation: Howard Associates, LLC , 3040 East Cornwallis Road, P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: James L
authors.initials: JL
authors.lastname: Howard
authors.affiliation: Research Triangle Institute , 3040 East Cornwallis Road, P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Fennell
authors.affiliation: Research Triangle Institute , 3040 East Cornwallis Road, P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: Rodney W
authors.initials: RW
authors.lastname: Snyder
authors.affiliation: Research Triangle Institute , 3040 East Cornwallis Road, P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004232:Diuretics / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009292:Narcotic Antagonists / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D010880:Piperidines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors
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; C551454:7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)methyl)-2-methylbutyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide dihydrochloride; D004232:Diuretics; D009292:Narcotic Antagonists; D010880:Piperidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
keywords: JDTic; brain; diuresis; pharmacokinetics; prodrug; rat; κ-opioid receptor antagonist