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
Straiker, Alex; Dvorakova, Michaela; Zimmowitch, Anaelle et al. (2018) Cannabidiol Inhibits Endocannabinoid Signaling in Autaptic Hippocampal Neurons. Mol Pharmacol 94:743-748
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Slivicki, Richard A; Saberi, Shahin A; Iyer, Vishakh et al. (2018) Brain-Permeant and -Impermeant Inhibitors of Fatty Acid Amide Hydrolase Synergize with the Opioid Analgesic Morphine to Suppress Chemotherapy-Induced Neuropathic Nociception Without Enhancing Effects of Morphine on Gastrointestinal Transit. J Pharmacol Exp Ther 367:551-563
Li, Ai-Ling; Carey, Lawrence M; Mackie, Ken et al. (2017) Cannabinoid CB2 Agonist GW405833 Suppresses Inflammatory and Neuropathic Pain through a CB1 Mechanism that is Independent of CB2 Receptors in Mice. J Pharmacol Exp Ther 362:296-305
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Ruehle, Sabine; Wager-Miller, James; Straiker, Alex et al. (2017) Discovery and characterization of two novel CB1 receptor splice variants with modified N-termini in mouse. J Neurochem 142:521-533
Hua, Tian; Vemuri, Kiran; Nikas, Spyros P et al. (2017) Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature 547:468-471
Dhopeshwarkar, Amey; Murataeva, Natalia; Makriyannis, Alex et al. (2017) Two Janus Cannabinoids That Are Both CB2 Agonists and CB1 Antagonists. J Pharmacol Exp Ther 360:300-311

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