This application, designed in response to RFA-DA-09-001, addresses the need for novel medications to manage cannabis dependence and addiction, recognized public health problems that are directly relevant to NIDA's mission. (-)-delta-9-Tetrahydrocannabinol (delta-9-THC), the principal active ingredient in illicitly smoked marijuana, is legally available in oral preparations (dronabinol) for the relief of pain and nausea associated with the occurrence or management of cancer or HIV/AIDS. Recently, it also has been shown to have positive effects in countering withdrawal symptoms that likely contribute to marijuana addiction and relapse. However, oral formulations of delta-9-THC suffer from a number of clinically unfavorable properties including poor bioavailability, erratic biodisposition, and unpredictable onsets and offsets of action. We propose to synthesize and efficiently identify novel cannabinoid agonists that will improve upon the pharmacological characteristics of delta-9-THC and that, consequently, may serve as viable medications for the management of cannabis dependence. In our chemistry program, we will modify delta-9-THC and nabilone to produce unique molecules that have improved 'druggability', i.e., increased polarity, water solubility, and designed for inactivation through enzymatic detoxification. In this 'soft drug'approach, the drug, after exercising its biological actions, is enzymatically inactivated to yield products with no or much lower activities. In our pharmacology program, we will use in vitro measures (receptor binding, functional efficacy, plasma and microsomal stability) and in vivo endpoints (brain penetrability, hypothermia, analgesia) to identify novel cannabinergic analogs that reliably enter the brain and have predictable time courses of action. Compounds with the most favorable preclinical characteristics will be evaluated in drug discrimination studies to gauge the presence and time course of THC-like 'subjective-like'effects. Finally, the most promising compounds will be given in repeated dosing regimens to evaluate their ability to counter withdrawal as well as their propensity to produce cannabinoid tolerance or dependence.

Public Health Relevance

This project is designed to develop novel medications for the clinical management of cannabis dependence and addiction. In this work, we aim to develop compounds with improved 'druggability', i.e., predictable and controllable time course and inactivation through detoxification to inactive metabolic products. We anticipate that such drugs will have utility for countering signs and symptoms of cannabis withdrawal and, consequently, the role of physical dependence in addiction to marijuana and other cannabis products.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA026795-04
Application #
8286379
Study Section
Special Emphasis Panel (ZDA1-MXH-H (01))
Program Officer
Shih, Ming L
Project Start
2009-07-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$562,171
Indirect Cost
$172,012
Name
Northeastern University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Kulkarni, Shashank; Nikas, Spyros P; Sharma, Rishi et al. (2016) Novel C-Ring-Hydroxy-Substituted Controlled Deactivation Cannabinergic Analogues. J Med Chem 59:6903-19
Makriyannis, Alexandros (2014) 2012 Division of medicinal chemistry award address. Trekking the cannabinoid road: a personal perspective. J Med Chem 57:3891-911
Desai, Rajeev I; Thakur, Ganesh A; Vemuri, V Kiran et al. (2013) Analysis of tolerance and behavioral/physical dependence during chronic CB1 agonist treatment: effects of CB1 agonists, antagonists, and noncannabinoid drugs. J Pharmacol Exp Ther 344:319-28
Kangas, Brian D; Delatte, Marcus S; Vemuri, V Kiran et al. (2013) Cannabinoid discrimination and antagonism by CB(1) neutral and inverse agonist antagonists. J Pharmacol Exp Ther 344:561-7
Paronis, Carol A; Thakur, Ganesh A; Bajaj, Shama et al. (2013) Diuretic effects of cannabinoids. J Pharmacol Exp Ther 344:8-14
Duclos Jr, Richard I; Johnston, Meghan; Vadivel, Subramanian K et al. (2011) A methodology for radiolabeling of the endocannabinoid 2-arachidonoylglycerol (2-AG). J Org Chem 76:2049-55
Järbe, Torbjörn U C; Gifford, Roger S; Makriyannis, Alexandros (2010) Antagonism of ??-THC induced behavioral effects by rimonabant: time course studies in rats. Eur J Pharmacol 648:133-8
Sink, K S; Segovia, K N; Nunes, E J et al. (2009) Intracerebroventricular administration of cannabinoid CB1 receptor antagonists AM251 and AM4113 fails to alter food-reinforced behavior in rats. Psychopharmacology (Berl) 206:223-32