Methamphetamine (METH) addiction is a global problem, and has now reached epidemic proportions in certain Western, Midwestern, and Southern states including North Carolina. Total abstinence from METH is very difficult to achieve in the clinic, mainly because, even after abstinence is achieved, addicts remain vulnerable for years to episodes of craving and relapse triggered by stimuli previously associated with drug abuse. Recent evidence suggests that certain protein kinase C (PKC) isoforms (e.g., PKC b2, y, s, z) may play important roles in the initiation, consolidation and/or long-term maintenance of drug abuse. In this regard, PKC z may be particularly important because this isoform appears to mediate maintenance of long-term potentiation (LTP), learning, and memory. Our preliminary studies have identified several small molecule PKC z inhibitors. The main goals of the present project are to design, synthesize, and screen small molecule libraries to identify and pharmacologically evaluate potent and isoform-specific PKC z inhibitors as potential treatment agents for METH addiction. First, 20,000 small molecules will be screened to identify more potent and isoform-specific inhibitors of PKC z enzymatic activity. Structure-activity relationship (SAR) and pharmacophore of PKC z inhibitors will be established. Second, cellular toxicity, PKC z inhibitory activity, efficacy, and specificity of hit compounds will be determined. Third, effects on total protein and phosphorylation levels of selected downstream targets in PKC z signaling pathways will be evaluated. Fourth, if the proposed research successfully identifies potent and isoform-specific small molecule PKC z inhibitors, these inhibitors will be tested for in vivo specificity, potency, and efficacy in METH sensitization and self-administration models. The proposed research represents a combination of synthetic organic chemistry and cell biology to broaden the number of available pharmacological interventions for METH addiction and thus promote long-term abstinence in humans. In addition to the clinical significance of the proposed studies, they are expected to provide new pharmacological tools for preclinical elucidation of novel neurobiological mechanisms underlying compulsive chronic psychostimulant abuse and neurotoxic effects of METH addiction.

Public Health Relevance

Protein kinase C (PKC) z may play important roles in the initiation, consolidation and/or long-term maintenance of drug abuse. The main goals of the proposed project are to design, synthesize, and screen small molecule libraries to identify and pharmacologically evaluate potent and isoform-specific PKC z inhibitors as potential treatment agents for methamphetamine (METH) addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Research Grants (R03)
Project #
5R03DA026562-02
Application #
7826641
Study Section
Special Emphasis Panel (ZRG1-MNPS-C (09))
Program Officer
Shih, Ming L
Project Start
2009-05-15
Project End
2011-12-30
Budget Start
2010-05-01
Budget End
2011-12-30
Support Year
2
Fiscal Year
2010
Total Cost
$196,250
Indirect Cost
Name
Duke University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Hong, Jiyong (2011) Role of natural product diversity in chemical biology. Curr Opin Chem Biol 15:350-4