The cannabinoid type-1 (CB1) receptor is a promising pharmacotherapeutic target for many diseases as evidenced by a large body of preclinical and clinical data showing efficacy treating drug dependence/addiction, pain, obesity/metabolic syndrome, and others. Unfortunately drugs developed that target the CB1 receptor either directly or indirectly have had limited success, i.e. dronabinol produces undesired psychoactivity, rimonabant produces depression/suicidal ideation, and PF-04457845 did not demonstrate efficacy. Important considerations in the therapeutic vs. nontherapeutic effects of CB1 activation are the various signaling pathways that contribute to either of these. Allosteric modulation provides an additional vector through which the CB1 receptor can be manipulated for therapeutic gain. This study proposes to 1) examine novel structural analogs of established CB1 allosteric modulators for their ability to alter orthosteric ligand binding, function, and signaling bias; 2) characterize G protein subtype-dependent coupling by orthosteric and allosteric ligands in N18TG2 cells which provide physiologically relevant receptor/G protein stoichiometry; and 3) assess the effects of CB1 allosteric modulators in assays of cannabinoid activity, opioid withdrawal and self-administration for determination of efficacy in therapeutically relevant models. My goals for this career development award are to build on my laboratory?s capabilities and prepare for independence as a principal investigator in the behavioral and molecular pharmacology of drug abuse. My laboratory currently has the capabilities to carry out the proposed studies but I require additional training in molecular pharmacology to learn G protein antibody capture scintillation proximity assay to complete Aim 2 which I will learn in Dr. Allyn Howlett?s laboratory. I will also learn complementary techniques in molecular biology in a workshop from New England BioLabs. I will also benefit from guidance in receptor theory, application of allosteric models and quantification of signaling bias which I will receive from my co-mentor Dr. Terry Kenakin. I also require training in self-administration for Aim 3 experiments which I will learn in Dr. Jenny Wiley?s laboratory. In addition to technical training, I require career development in order prepare for research independence. Under this award I will receive training in grantsmanship, laboratory management, budget management, and responsible conduct of research. These career development activities will include one-on-one training with co-mentors as well as workshops to provide me with necessary training to successfully compete for R01 funding and develop a highly productive and efficient independent research program.
The cannabinoid type-1 receptor is a promising therapeutic target but strategies involving orthosteric interaction with the receptor have been hindered by their propensity to produce side effects. CB1 allosteric modulators are an alternate strategy to affect receptor signaling and bias to target therapeutically relevant signaling pathways. We propose to systematically assess novel CB1 allosteric modulators for signaling bias and test select compounds in behavioral assays of cannabinoid activity and therapeutic relevance.
| Nguyen, Thuy; Gamage, Thomas F; Decker, Ann M et al. (2018) Diarylureas Containing 5-Membered Heterocycles as CB1 Receptor Allosteric Modulators: Design, Synthesis, and Pharmacological Evaluation. ACS Chem Neurosci : |
