The endocannabinoid system plays a critical role in several diseases, including drug dependence. The long-term objective of this application is to understand the role that CB1, CB2 and orphan G-protein-coupled receptors play in these processes. Presently, CB1 receptor agonists act both centrally and peripherally and as well as at CB2 receptors. We propose to develop new CB1 receptor agonists that lack CB2 receptor affinity and/or are restricted to the periphery. Considerable emphasis will be placed on CB1 receptor allosteric modulators as we predict they will produce a pharmacological profile distinct from orthosteric ligands. Furthermore, perturbation of the endocannabinoid system in disease states could be due to either alterations in endocannabinoid levels or constitutive receptor activity, processes that are not easily distinguished by current CB1 receptor inverse agonists/antagonists. Therefore, we will pursue new leads in developing neutral CB1 receptor antagonists that will act solely to block endocannabinoids. Since both CB1 and CB2 receptors exhibit anti-inflammatory and analgesic properties, we propose to fully characterize these properties of CB2 selective agonists that we developed during the current funding period. In addition, we will determine the degree of tolerance that these CB2 selective agonists produce. There is now ample evidence that additional cannabinoid receptor subtypes exist, including several orphan G-protein-coupled receptors. One of our goals is to determine whether GPR55 is a cannabinoid receptor, and if so, what is its pharmacological properties and contribution to drug dependence. Based upon many years of experience, we have developed an evaluation screen that allows us to prioritize new compounds for analysis. Initial evaluation in CB1 and CB2 receptor binding and function assays allow us to determine which compounds will be evaluated in vivo using the mouse tetrad or in situ using smooth muscle preparations. Subsequent analysis will include acute and chronic pain models, drug discrimination, tolerance and dependence protocols as appropriate for individual specific aims. We will also employ CB1, CB2, and GPR55 knockout mice as necessary. New cannabinoid orthosteric agonists and allosteric modulators for CB1, CB2 and new cannabinoid receptors, as well as neutral antagonists, hold promise as therapeutic agents for treatment of drug dependence, chronic pain, and other neurological disorders.

Public Health Relevance

The goal of this project is to gain a better understanding of the role that the endocannabinoid system plays in pain perception and drug addiction. We propose to develop new drugs for investigating the endocannabinoid system. These drugs will also have potential use as analgesics and drug abuse medications.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003672-28
Application #
8033227
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Rapaka, Rao
Project Start
1984-09-01
Project End
2013-02-28
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
28
Fiscal Year
2011
Total Cost
$427,839
Indirect Cost
Name
Research Triangle Institute
Department
Type
DUNS #
004868105
City
Research Triangle
State
NC
Country
United States
Zip Code
27709
Wiley, Jenny L; Lefever, Timothy W; Marusich, Julie A et al. (2017) Comparison of the discriminative stimulus and response rate effects of ?9-tetrahydrocannabinol and synthetic cannabinoids in female and male rats. Drug Alcohol Depend 172:51-59
Kevin, Richard C; Lefever, Timothy W; Snyder, Rodney W et al. (2017) Kinetic and metabolic profiles of synthetic cannabinoids NNEI and MN-18. Drug Test Anal :
Owens, Robert A; Mustafa, Mohammed A; Ignatowska-Jankowska, Bogna M et al. (2017) Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice. Neuropharmacology 125:80-86
Nguyen, Thuy; Li, Jun-Xu; Thomas, Brian F et al. (2017) Allosteric Modulation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor. Med Res Rev 37:441-474
Gamage, Thomas F; Farquhar, Charlotte E; Lefever, Timothy W et al. (2017) The great divide: Separation between in vitro and in vivo effects of PSNCBAM-based CB1 receptor allosteric modulators. Neuropharmacology 125:365-375
Wiley, Jenny L; Marusich, Julie A; Thomas, Brian F (2017) Combination Chemistry: Structure-Activity Relationships of Novel Psychoactive Cannabinoids. Curr Top Behav Neurosci 32:231-248
Grim, T W; Morales, A J; Thomas, B F et al. (2017) Apparent CB1 Receptor Rimonabant Affinity Estimates: Combination with THC and Synthetic Cannabinoids in the Mouse In Vivo Triad Model. J Pharmacol Exp Ther 362:210-218
Lefever, Timothy W; Lee, Youn O K; Kovach, Alexander L et al. (2017) Delivery of nicotine aerosol to mice via a modified electronic cigarette device. Drug Alcohol Depend 172:80-87
Marusich, Julie A; Wiley, Jenny L; Lefever, Timothy W et al. (2017) Finding order in chemical chaos - Continuing characterization of synthetic cannabinoid receptor agonists. Neuropharmacology :
Thomas, Brian F; Lefever, Timothy W; Cortes, Ricardo A et al. (2017) Thermolytic Degradation of Synthetic Cannabinoids: Chemical Exposures and Pharmacological Consequences. J Pharmacol Exp Ther 361:162-171

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