The broad, long-term goal of this application is to discover and develop pharmacotherapies for the treatment of substance abuse. Specifically, we will develop potent and selective kappa opioid receptor antagonists to treat opiate addicts in withdrawal, including relapse to the opiates. Selective kappa opioid antagonists may also be useful in preventing relapse to cocaine addiction. Potent and selective delta opioid receptor antagonists have potential as pharmacotherapies to prevent relapse to opiates, cocaine, and alcohol abuse. Importantly, compounds developed will also serve as biochemical and pharmacological probes useful in gaining a better understanding of the biochemical and molecular mechanisms of opiate, cocaine, and alcohol addiction. Significant research findings directed toward the specific aims of the current grant were achieved. We discovered JDTic and (-)-KAA1 as potent and selective K opioid receptor antagonists and (+)-KF4 as a potent and selective d opioid receptor antagonist that is also an inverse agonist. All three compounds are small molecules that will penetrate the CNS and have high stability. Thus, all three are highly useful lead structures for the development of pharmacotherapies for treating substance abuse. The unique pharmacological properties of JDTic have already led to its selection for preclinical development. This application is for continuing support of the present program. The proposed research continues to be based on the original hypothesis that pharmacotherapies for treating substance abuse can be discovered and developed through lead optimization of novel compounds from the opioid research area. The scope of the proposed studies will involve: (1) design and synthesis of novel lead structures based on the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, 4beta-and 9beta-methyl-5-(3-hydroxyphenyl)morphan, and 4a-(3-hydroxyphenyl)-8a-methyldecahydroisoquinoline classes of opioid antagonists; (2) in vitro evaluation of compounds using radioligand binding and [35S]GTPgammaS functional assays; and (3) in vivo evaluation of potent kappa and delta selective antagonists discovered for their effects on kappa and delta agonist-induced diuresis and antinociception in rat models. Selected compounds will be submitted to the NIDA Opioid Treatment Discovery Program (OTDP) for evaluation in a mouse antinociceptive assay, foot shock-induced reinstatement of responding for heroin and cocaine in rat models, and morphine-induced physically dependent rat model. Compounds that are potent delta selective opioid receptor inverse agonists will be evaluated by Dr. Chris Evans (UCLA) in a chronic antinociception rat model.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009045-11
Application #
6928976
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Hillery, Paul
Project Start
1994-08-15
Project End
2009-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
11
Fiscal Year
2005
Total Cost
$462,531
Indirect Cost
Name
Research Triangle Institute
Department
Type
DUNS #
004868105
City
Research Triangle
State
NC
Country
United States
Zip Code
27709
Lazenka, Matthew L; Moerke, Megan J; Townsend, E Andrew et al. (2018) Dissociable effects of the kappa opioid receptor agonist nalfurafine on pain/itch-stimulated and pain/itch-depressed behaviors in male rats. Psychopharmacology (Berl) 235:203-213
Kormos, Chad M; Ondachi, Pauline W; Runyon, Scott P et al. (2017) Simple Tetrahydroisoquinolines Are Potent and Selective Kappa Opioid Receptor Antagonists. ACS Med Chem Lett 8:742-745
Wells, Audrey M; Ridener, Elysia; Bourbonais, Clinton A et al. (2017) Effects of Chronic Social Defeat Stress on Sleep and Circadian Rhythms Are Mitigated by Kappa-Opioid Receptor Antagonism. J Neurosci 37:7656-7668
Runyon, Scott P; Kormos, Chad M; Gichinga, Moses G et al. (2016) Design, Synthesis, and Biological Evaluation of Structurally Rigid Analogues of 4-(3-Hydroxyphenyl)piperidine Opioid Receptor Antagonists. J Org Chem 81:10383-10391
Kormos, Chad M; Gichinga, Moses G; Runyon, Scott P et al. (2016) Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of replacement of the 3-hydroxyphenyl group with pyridine or thiophene bioisosteres. Bioorg Med Chem 24:3842-8
Donahue, Rachel J; Landino, Samantha M; Golden, Sam A et al. (2015) Effects of acute and chronic social defeat stress are differentially mediated by the dynorphin/kappa-opioid receptor system. Behav Pharmacol 26:654-63
Buda, Jeffrey J; Carroll, F I; Kosten, Thomas R et al. (2015) A Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of JDTic. Neuropsychopharmacology 40:2059-65
Taylor, A M W; Roberts, K W; Pradhan, A A et al. (2015) Anti-nociception mediated by a ? opioid receptor agonist is blocked by a ? receptor agonist. Br J Pharmacol 172:691-703
Carroll, F Ivy; Gichinga, Moses G; Kormos, Chad M et al. (2015) Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of the 3- and 4-methyl substituents. Bioorg Med Chem 23:6379-88
Carroll, F Ivy; Dolle, Roland E (2014) The discovery and development of the N-substituted trans-3,4-dimethyl-4-(3'-hydroxyphenyl)piperidine class of pure opioid receptor antagonists. ChemMedChem 9:1638-54

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