RESEARCH & RELATED - OTHER PROJECT INFORMATION - PROJECT SUMMARY/ABSTRACT The goal of the Program Project is to explore the functional properties of the CB1 and CB2 cannabinoid receptors through the development of suitable novel ligands and by obtaining structural and functional information on these receptors. During the current cycle, we have developed high-affinity covalent and non- covalent CB1/CB2 ligands to study their foot-printing at the receptor using a Ligand Assisted Protein Structure (LAPS) approach which includes the use of covalent ligands, receptor mutants and LC/MS/MS methods. The results are further elaborated using computationally-derived receptor models. To date, our results provide initial evidence that different classes of cannabinergic ligands interact and activate/deactivate the CB1 and CB2 receptors through distinct binding motifs associated with distinct ligand-receptor conformations. In parallel with our ligand and CB1/CB2 structural work, our collaborators have provided evidence that CB1 (Bohn) and CB2 (Mackie) different agonists activate these receptors through distinct signaling pathways (functional selectivity). We have hypothesized that the individual ligand- receptor binding motifs we have identified, in turn, may be associated with distinct identifiable signaling pathways leading to different ligand-associated pharmacological profiles. A central theme for this Program Project renewal application is that distinct signaling profiles identified within CB1 and CB2 will allow us to design functionally selective ligands. This novel functional pharmacophore-based drug design should lead to new ligands with improved pharmacological profiles. This Program Project renewal proposes to: 1) design and synthesize first and later generation covalent and non-covalent ligands to be used to probe the functional properties and binding motifs of the key classes of cannabinergic ligands; 2) identify the binding motifs of the covalent ligands by using receptor mutants and LC/MS/MS methods; 3) Identify CB1 and CB2 signaling profiles of the most successful ligands; and 4) evaluate in vivo the CB1 and CB2 ligands using the mouse tetrad test as well as in animal models for neuropathic pain. The results to be obtained will serve as a basis for the development for therapies for addiction and pain.

Public Health Relevance

RESEARCH & RELATED - OTHER PROJECT INFORMATION - PROJECT NARRATIVE This PPG renewal proposes to study the signaling mechanisms of cannabinergic compounds and the design and synthesis of probes with improved pharmacological profiles. The results can be used to develop improved therapies for addiction and pain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA009158-18
Application #
9320724
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hillery, Paul
Project Start
1994-09-15
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
18
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Northeastern University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
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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
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; Xu, Zhili; Kulkarni, Pushkar M et al. (2018) Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence. Biol Psychiatry 84:722-733
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
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
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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