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)
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Special Emphasis Panel (ZRG1)
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Northeastern University
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Deng, Liting; Guindon, Josée; Cornett, Benjamin L et al. (2015) Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal. Biol Psychiatry 77:475-87
Tyukhtenko, Sergiy; Chan, Karrie; Jiang, Rubin et al. (2015) Hydrogen-bonded His93 as a sensitive probe for identifying inhibitors of the endocannabinoid transport protein FABP7. Chem Biol Drug Des 85:534-40
Rahn, Elizabeth J; Deng, Liting; Thakur, Ganesh A et al. (2014) Prophylactic cannabinoid administration blocks the development of paclitaxel-induced neuropathic nociception during analgesic treatment and following cessation of drug delivery. Mol Pain 10:27
Makriyannis, Alexandros (2014) 2012 Division of medicinal chemistry award address. Trekking the cannabinoid road: a personal perspective. J Med Chem 57:3891-911
Jarbe, Torbjorn U C; LeMay, Brian J; Halikhedkar, Aneetha et al. (2014) Differentiation between low- and high-efficacy CB1 receptor agonists using a drug discrimination protocol for rats. Psychopharmacology (Berl) 231:489-500
Sharma, Rishi; Nikas, Spyros P; Guo, Jason Jianxin et al. (2014) C-ring cannabinoid lactones: a novel cannabinergic chemotype. ACS Med Chem Lett 5:400-4
Nasr, Mahmoud L; Shi, Xiaomeng; Bowman, Anna L et al. (2013) Membrane phospholipid bilayer as a determinant of monoacylglycerol lipase kinetic profile and conformational repertoire. Protein Sci 22:774-87
Thakur, Ganesh A; Bajaj, Shama; Paronis, Carol et al. (2013) Novel adamantyl cannabinoids as CB1 receptor probes. J Med Chem 56:3904-21
Karageorgos, Ioannis; Wales, Thomas E; Janero, David R et al. (2013) Active-site inhibitors modulate the dynamic properties of human monoacylglycerol lipase: a hydrogen exchange mass spectrometry study. Biochemistry 52:5016-26
West, Jay M; Zvonok, Nikolai; Whitten, Kyle M et al. (2012) Mass spectrometric characterization of human N-acylethanolamine-hydrolyzing acid amidase. J Proteome Res 11:972-81

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