The endocannabinoid system plays a major role in modulating pain perception and mood and therefore, ligands that act at the cannabinoid receptors may prove to have wide-ranging therapeutic utility. Prior drug development efforts at the CB1 receptor have involved using one-dimensional signaling outputs to determine overall efficacy and potency. However, recent advances in understanding receptor pharmacology indicate that receptors are capable of engaging in multiple signaling cascades and that the chemical nature of the ligand can direct these downstream signaling pathways. Furthermore, there is increasing evidence that diverse signaling pathways can give rise to distinct physiological responses produced by a drug. This paradigm yields a novel manner by which to fine-tune receptor signaling in order to enhance desirable biological effects (such as pain relief) while simultaneously eliminating unwanted side effects (such as sedation or negative effects on mood). The project described herein is focused on the characterization of functionally selective ligands at the CB1 cannabinoid receptor. We hypothesize that ligands that bind to certain regions of the receptor will lead to different signaling profiles than those that bind to other regions. Moreover, our goal is to use probe compounds characterized for such functional selectivity to determine if they induce certain behavioral responses while sparing other physiological responses. To this end we will work closely with Project 1 to evaluate compounds that are shown to bind to particular residues in the CB1R in multiple signaling assays, validate signaling in neurons (AIM 1) and then test behaviors in mice (AIM 2, Project 3). The development of such important tools will not only serve to allow for the testing the hypothesis that functional selectivity can fine tune drug efficacies in vivo, but may also serve as the building blocks for the development of future therapeutics for pain, depression and addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
2P01DA009158-15A1
Application #
8742284
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
Budget Start
2014-09-15
Budget End
2015-06-30
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Northeastern University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
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
Deng, Liting; Lee, Wan-Hung; Xu, Zhili et al. (2016) Prophylactic treatment with the tricyclic antidepressant desipramine prevents development of paclitaxel-induced neuropathic pain through activation of endogenous analgesic systems. Pharmacol Res 114:75-89
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
Dhopeshwarkar, Amey; Mackie, Ken (2016) Functional Selectivity of CB2 Cannabinoid Receptor Ligands at a Canonical and Noncanonical Pathway. J Pharmacol Exp Ther 358:342-51
Kulkarni, Pushkar M; Kulkarni, Abhijit R; Korde, Anisha et al. (2016) Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s). J Med Chem 59:44-60
Järbe, Torbjörn U C; LeMay, Brian J; Thakur, Ganesh A et al. (2016) A high efficacy cannabinergic ligand (AM4054) used as a discriminative stimulus: Generalization to other adamantyl analogs and Δ(9)-THC in rats. Pharmacol Biochem Behav 148:46-52
Carey, Lawrence M; Slivicki, Richard A; Leishman, Emma et al. (2016) A pro-nociceptive phenotype unmasked in mice lacking fatty-acid amide hydrolase. Mol Pain 12:
Hua, Tian; Vemuri, Kiran; Pu, Mengchen et al. (2016) Crystal Structure of the Human Cannabinoid Receptor CB1. Cell 167:750-762.e14
Schindler, Charles W; Scherma, Maria; Redhi, Godfrey H et al. (2016) Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys. Psychopharmacology (Berl) 233:1867-77
Panlilio, Leigh V; Thorndike, Eric B; Nikas, Spyros P et al. (2016) Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats. Psychopharmacology (Berl) 233:1879-88

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