This Program Project (PP) application represents a comprehensive collaborative effort to obtain information on the endocannabinoid sites of action that will ultimately be used to develop novel therapeutic drug analogs. The application work will seek to explore the pharmacophoric requirements for activation/deactivation/desensitization of the CB1 and CB2 cannabinoid receptors. It also includes efforts to successfully image the CB1 binding sites. During the current funding period, we have made very substantial progress in the above goals and also developed novel approaches which are now being integrated in our current submission. The goals of this competing renewal are further refined and extended to address important developments in the field, some of which were generated under the auspices of this PP. This PP will seek to obtain detailed knowledge on the structure, function and distribution of the CB1 and CB2 cannabinoid receptors. The information will serve as a basis for the design of new drug molecules with selectivity for these two receptors. The work will be accomplished through an integrated interdisciplinary effort centered around the development of high affinity ligands from the different classes of CBics and includes: (a) obtaining information on the CB1 and CB2 binding sites using covalent and non-covalent ligands. The pharmacophoric requirements for the two receptors will be compared to those of the endocannabinoid deactivating enzymes (FAAH, MGL and COX2) and the transporter system (ANT); (b) the in vivo imaging of CB1 receptors, in mammalian brains using PET and SPECT (future work will seek to in vivo image other cannabinergic targets in the brain using methods developed here); (c) defining the pharmacophoric features of a ligand associated with CB1 and CB2 activation and desensitization and developing selective ligands for each of the two processes. The role of CBR dimerization will also be explored. The PP will involve an intense joint effort between collaborating laboratories committed to utilize common resources and share information in order to accomplish common goals in an efficient, effective and highly synergistic manner. The information from the proposed work will be used to develop novel therapies for combating drug addiction and developing non-addictive medications for the management of pain and nausea. These may prove to be important for combating the scourge of addiction and should be contributions of great value to public health. ? ? ? ? ? ? PROGRAM CHARACTERISTICS ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA009158-11
Application #
7423877
Study Section
Special Emphasis Panel (ZDA1-RXL-E (16))
Program Officer
Hillery, Paul
Project Start
1994-09-30
Project End
2012-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
11
Fiscal Year
2008
Total Cost
$1,102,420
Indirect Cost
Name
Northeastern University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Lin, Xiaoyan; Dhopeshwarkar, Amey S; Huibregtse, Megan et al. (2018) Slowly Signaling G Protein-Biased CB2 Cannabinoid Receptor Agonist LY2828360 Suppresses Neuropathic Pain with Sustained Efficacy and Attenuates Morphine Tolerance and Dependence. Mol Pharmacol 93:49-62
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
Mallipeddi, Srikrishnan; Zvonok, Nikolai; Makriyannis, Alexandros (2018) Expression, Purification and Characterization of the Human Cannabinoid 1 Receptor. Sci Rep 8:2935
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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