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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Special Emphasis Panel (ZRG1)
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Northeastern University
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Hua, Tian; Vemuri, Kiran; Nikas, Spyros P et al. (2017) Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature 547:468-471
Slivicki, Richard A; Xu, Zhili; Kulkarni, Pushkar M et al. (2017) Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence. Biol Psychiatry :
Finlay, David B; Cawston, Erin E; Grimsey, Natasha L et al. (2017) G?s signalling of the CB1 receptor and the influence of receptor number. Br J Pharmacol 174:2545-2562
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
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
Mallipeddi, Srikrishnan; Janero, David R; Zvonok, Nikolai et al. (2017) Functional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets. Biochem Pharmacol 128:1-11
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
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
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 ?(9)-THC in rats. Pharmacol Biochem Behav 148:46-52
Hua, Tian; Vemuri, Kiran; Pu, Mengchen et al. (2016) Crystal Structure of the Human Cannabinoid Receptor CB1. Cell 167:750-762.e14

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