PAS-06-Q66 identifies a need for novel directions in the development of medications against drug addictions. To answer this need, we plan to synthesize and pharmacologically evaluate novel cannabinergic-1 (CB1) partial agonists and antagonists for the management of methamphetamine addiction. Methamphetamine addiction has become a world-wide epidemic, and is recognized as the most serious drug abuse problem in this country today. Addiction to methamphetamine, like other abused drugs, can be characterized as a recurring disease involving abuse, addiction, transition to drug-free status, and relapse. Different medications may be effective at different points in the cycle. We propose that CB1 partial agonists, through actions that overlap those of methamphetamine, may-assist in the transition to drug-free status and that CB1 antagonists, by dampening or masking the effects of stimuli that trigger drug-seeking behavior, may help prevent relapse. Our approach is based upon an emerging literature and our own laboratory observations indicating that a) CB1 agonists and methamphetamine have convergent neurochemical and behavioral actions;and b) CB1 antagonists may lessen the impact of drugs or conditions that instigate drug-seeking behavior. In our proposed research, we will use chemical templates that we and others have developed for cannabinergic ligands to design and construct novel lead compounds. Our goal is to generate analogs that vary in duration of action and pharmacological efficacy and will include both partial agonists and antagonists with neutral or inverse agonist activity. Our strategy will be to conduct side-by-side comparisons with the partial agonist A9THC and the inverse agonist SR141716A whenever possible. Novel CB1 ligands that meet efficacy criteria in biochemical studies will then be studied in rats to confirm their biological activity in hypothermia and drug discrimination studies. Next, we will use drug discrimination procedures to evaluate overlap in the 'subjective'effects of methamphetamine and novel CB1 partial agonists and, also, the ability of B1 antagonists to mute methamphetamine's stimulus effects. Finally, the most promising CB1 ligands will be further evaluated in our i.v. self-administration food/drug 'choice'procedures. We expect CB1 partial agonists to reduce methamphetamine's reinforcing strength, i.e., the proportion of behavior that it commands. We also expect CB1 antagonists to dampen the ability of low doses of noncontingently delivered methamphetamine to engender drug-seeking behavior, i.e., re-allocation of behavior toward i.v. injections and away from non-drug reinforcement. Overall, our proposed studies will permit highly significant progress toward the identification of cannabinergic candidates for drug development and, eventually, novel cannabinergic medications to combat different phases of methamphetamine addiction. This will be a significant contribution to the improvement of public health.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DA023142-03
Application #
7623583
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Shih, Ming L
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
3
Fiscal Year
2009
Total Cost
$691,419
Indirect Cost
Name
Northeastern University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Paronis, Carol A; Chopda, Girish R; Vemuri, Kiran et al. (2018) Long-Lasting In Vivo Effects of the Cannabinoid CB1 Antagonist AM6538. J Pharmacol Exp Ther 364:485-493
Hua, Tian; Vemuri, Kiran; Nikas, Spyros P et al. (2017) Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature 547:468-471
Thompson, Emily E; Jagielo-Miller, Julia E; Vemuri, V Kiran et al. (2016) CB1 antagonism produces behaviors more consistent with satiety than reduced reward value in food-maintained responding in rats. J Psychopharmacol 30:482-91
Jacobs, David S; Kohut, Stephen J; Jiang, Shan et al. (2016) Acute and chronic effects of cannabidiol on ??-tetrahydrocannabinol (??-THC)-induced disruption in stop signal task performance. Exp Clin Psychopharmacol 24:320-330
Hua, Tian; Vemuri, Kiran; Pu, Mengchen et al. (2016) Crystal Structure of the Human Cannabinoid Receptor CB1. Cell 167:750-762.e14
Järbe, Torbjörn U C; Gifford, Roger S; Zvonok, Alexander et al. (2016) [INCREMENT]9-Tetrahydrocannabinol discriminative stimulus effects of AM2201 and related aminoalkylindole analogs in rats. Behav Pharmacol 27:211-4
Gueye, Aliou B; Pryslawsky, Yaroslaw; Trigo, Jose M et al. (2016) The CB1 Neutral Antagonist AM4113 Retains the Therapeutic Efficacy of the Inverse Agonist Rimonabant for Nicotine Dependence and Weight Loss with Better Psychiatric Tolerability. Int J Neuropsychopharmacol 19:
Schindler, Charles W; Redhi, Godfrey H; Vemuri, Kiran et al. (2016) Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys. Neuropsychopharmacology 41:2283-93
Bowles, Nicole P; Karatsoreos, Ilia N; Li, Xiaosong et al. (2015) A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome. Proc Natl Acad Sci U S A 112:285-90
Keenan, C M; Storr, M A; Thakur, G A et al. (2015) AM841, a covalent cannabinoid ligand, powerfully slows gastrointestinal motility in normal and stressed mice in a peripherally restricted manner. Br J Pharmacol 172:2406-18

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