The broad, long-term goal of this application is to discover and develop pharmacotherapies for the treatment of substance abuse. Since stress can increase drug-taking behavior, we will develop potent and selective ? opioid receptor antagonists as potential new pharmacotherapies to help addicts not relapse to drug taking. Importantly, compounds developed will also serve as biochemical and pharmacological probes useful in gaining a better understanding of the biochemical and molecular mechanisms of cocaine, methamphetamine, nicotine, alcohol, and opiate addictions. Significant research findings directed toward the specific aims of the current grant were achieved. Our progress to date has led to the identification of several compounds that are potent and selective : opioid receptor antagonists in in vitro efficacy assays. The compounds are small molecules that are expected to penetrate the CNS and have high stability. Thus, these compounds are highly useful lead structures that require further development in pharmacokinetic (PK) and animal behavioral studies before their merit as potential pharmacotherapies for treating substance abuse can be determined. 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 receptor research area. Our general approach will be to design and synthesize compounds based on the (a) trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, (b) 42- and 92-methyl-5-(3-hydroxy- phenyl)morphan, (c) 4a-(3-hydroxyphenyl)-8a-methyldecahydroisoquinoline, (d) 3-[4-(substituted piperazin-1- yl)]phenol, and (e) N-substituted 4-(3-hydroxyphenyl)-4-methylazabicyclo[3.1.0]hexane classes of opioid antagonist. The merit of the compounds as potent and selective ? opioid antagonists will be obtained by monitoring the ability of the test compounds to inhibit stimulated [35S]GTP3S binding produced by selective ?, d, and ? agonists using cloned human opioid receptors expressed in CHO cells. Analogs meeting set criteria for ? potency and selectivity will be evaluated in an in vivo PK study to determine the ability of the compounds to cross the blood-brain barrier (BBB) and to have an appropriate half-life (t1/2). Compounds that have high potency and selectivity for ? opioid receptors and that have suitable brain levels and t1/2 values in the PK studies will be evaluated for their ability to antagonize ? selective agonist U50,488-induced diuresis in rats in order to establish their ? opioid receptor antagonist profile (potency and duration of action relative to JDTic). Information generated will be used to select compounds for evaluation in a foot-shock-induced reinstatement of responding for cocaine relapse test. Compounds that show AD50 values in this test comparable to the AD50 of the ? opioid antagonist JDTic, which is in preclinical development, will warrant further development.

Public Health Relevance

Drug abuse, addiction, and dependence remain major threats to public health. Development of new pharmacotherapies to treat cocaine, methamphetamine, nicotine, heroin, and ethanol addictions would be a major medical and societal breakthrough. This application addresses these problems by proposing to identify and develop selective ? opioid receptor antagonists as new pharmacotherapies to treat patients addicted to drugs of abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009045-18
Application #
8485550
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (91))
Program Officer
Kline, Richard
Project Start
1994-08-15
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
18
Fiscal Year
2013
Total Cost
$376,894
Indirect Cost
$178,699
Name
Research Triangle Institute
Department
Type
DUNS #
004868105
City
Research Triangle
State
NC
Country
United States
Zip Code
27709
Kormos, Chad M; Cueva, Juan Pablo; Gichinga, Moses G et al. (2014) Effect of the 3- and 4-methyl groups on the opioid receptor properties of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines. J Med Chem 57:3140-7
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
Kormos, Chad M; Gichinga, Moses G; Maitra, Rangan et al. (2014) 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 profil J Med Chem 57:7367-81
Carroll, F Ivy; Carlezon Jr, William A (2013) Development of ýý opioid receptor antagonists. J Med Chem 56:2178-95
Munro, Thomas A; Huang, Xi-Ping; Inglese, Carmela et al. (2013) Selective * opioid antagonists nor-BNI, GNTI and JDTic have low affinities for non-opioid receptors and transporters. PLoS One 8:e70701
Carroll, F Ivy; Gichinga, Moses G; Williams, John D et al. (2013) 4*-Methyl-5-(3-hydroxyphenyl)morphan opioid agonist and partial agonist derived from a 4*-methyl-5-(3-hydroxyphenyl)morphan pure antagonist. J Med Chem 56:8826-33
Kormos, Chad M; Jin, Chunyang; Cueva, Juan Pablo et al. (2013) Discovery of N-{4-[(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide analogues as selective kappa opioid receptor antagonists. J Med Chem 56:4551-67
Wu, Huixian; Wacker, Daniel; Mileni, Mauro et al. (2012) Structure of the human ?-opioid receptor in complex with JDTic. Nature 485:327-32
Schank, Jesse R; Goldstein, Andrea L; Rowe, Kelly E et al. (2012) The kappa opioid receptor antagonist JDTic attenuates alcohol seeking and withdrawal anxiety. Addict Biol 17:634-47
Deehan Jr, Gerald A; McKinzie, David L; Carroll, F Ivy et al. (2012) The long-lasting effects of JDTic, a kappa opioid receptor antagonist, on the expression of ethanol-seeking behavior and the relapse drinking of female alcohol-preferring (P) rats. Pharmacol Biochem Behav 101:581-7

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