This application is in response to RFA-DA-07-006 to design, synthesize and test in relevant preclinical models, potential treatments for drug addiction. The pharmacological approach proposed is to develop new classes of potent and selective orexin-1 (OX1) receptor antagonists that may prove efficacious in preventing relapse in abstinent human cocaine addicts. To accomplish this aim, we have assembled a team of highly motivated researchers with expertise in every aspect of the drug discovery process and in animal models of addiction.
Specific Aim I will involve establishing a robust in vitro cell-based functional assays for OX1 receptors (and appropriate counter-screens) which can support a medicinal chemistry program aimed at developing new classes of potent and selective OX1 receptor antagonists. Specifically, we will examine changes in agonist-induced increases of intracellular calcium signaling via membrane potential dyes and a fluorescent plate reader (FLIPR) in CHO cells stably expressing human OX1 receptors (OX1 receptors couple to Gq).In addition, we will establish a novel agonist-induced, G-protein-independent, receptor internalization assay coupled with high content imaging to make quantitative measurements of 0X1 receptor internalization upon agonist stimulation in U20S cells stably expressing OX1 receptors. This internalization assay will provide a counter-screen to the calcium signaling assays.
Specific Aim II will utilize an iterative medicinal chemistry program based on structure-activity relationships (SAR) to discover new classes of potent and selective OX1 receptor antagonists. Structure-activity relationships will be employed to optimize new classes of OX1 receptor antagonists for drug metabolism and pharmacokinetics (DMPK), and brain penetration properties.
Specific Aim III will test new classes of potent and selective OX1 receptor antagonists with favorable DMPK and brain penetration in the rat stress-induced reinstatement model of relapse to cocaine seeking. In addition, the intrinsic rewarding properties of OX1 receptor antagonists that block relapse-like behavior will be assessed in the intracranial self-stimulation (ICSS) thresholds procedure in rats in order to triage compounds with potential abuse liability. Such an integrated multidisciplinary research plan will capitalize on the unique drug discovery capabilities at Scripps Florida, and promises to yield novel therapeutic entities for the prevention of relapse in human addicts. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA023915-02
Application #
7496983
Study Section
Special Emphasis Panel (ZDA1-MXS-M (17))
Program Officer
Shih, Ming L
Project Start
2007-09-15
Project End
2012-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
2
Fiscal Year
2008
Total Cost
$424,095
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Muschamp, John W; Hollander, Jonathan A; Thompson, Jennifer L et al. (2014) Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area. Proc Natl Acad Sci U S A 111:E1648-55
Jiang, Rong; Song, Xinyi; Bali, Purva et al. (2012) Disubstituted piperidines as potent orexin (hypocretin) receptor antagonists. Bioorg Med Chem Lett 22:3890-4
Zhou, Luyi; Ghee, Shannon M; Chan, Clifford et al. (2012) Orexin-1 receptor mediation of cocaine seeking in male and female rats. J Pharmacol Exp Ther 340:801-9
Kenny, Paul J (2011) Tobacco dependence, the insular cortex and the hypocretin connection. Pharmacol Biochem Behav 97:700-7
Hollander, Jonathan A; Lu, Qun; Cameron, Michael D et al. (2008) Insular hypocretin transmission regulates nicotine reward. Proc Natl Acad Sci U S A 105:19480-5