The long term goal of this research project is to elucidate the basis for the actions of the cannabinoids (CBs) at the molecular level. To this end, we are developing the elements of an understanding of the relationships between cannabinoid ligand structure;cannabinoid receptor structure;and cannabinoid receptor activation at an atomic level of detail. The research plan includes two emphases: ligand-receptor recognition and ligand-induced receptor activation/inactivation and is based upon 3D computer models of the CB1 and CB2 receptors that we have developed and refined during the current grant period. Our recent microsecond timescale molecular dynamics simulations of the CB2 receptor in a POPC bilayer have yielded important insights concerning the differences between CB1 and CB2. We will use this information here to explore the interactions important for the maintenance of the CB2 receptor inactive state and those responsible for the generation of the CB2 activated state. A binding site model for CB2 inverse agonists/antagonists will be developed in order to identify those interactions necessary for the production of inverse agonism at CB2. Studies will also be undertaken to identify the interaction site(s) for novel CB1 allosteric modulators with the goal of designing more potent modulators. At each step, our work will be aided and supplemented by collaboration with experimental medicinal chemists, molecular biologists and pharmacologists. Collaborative studies will be used to test our models in an iterative fashion with the goal that these models represent the current state of knowledge in the cannabinoid field. The information about cannabinoid receptor structure and binding modes of ligands that will emerge from the collaborative studies proposed here will aid in fundamental structure-function studies of this important class of receptors and will also aid in the design of improved therapeutic agents based on the cannabinoids.

Public Health Relevance

The long term goal of this research project is to elucidate the basis for the actions of the cannabinoids (CBs) at the molecular level. To this end, we are developing the elements of an understanding of the relationships between cannabinoid ligand structure;cannabinoid receptor structure;and cannabinoid receptor activation at an atomic level of detail. The research plan includes two emphases: ligand-receptor recognition and ligand-induced receptor activation/inactivation and is based upon 3D computer models of the CB1 and CB2 receptors that we have developed and refined during the current grant period. Results of the studies proposed here have the potential for the development of therapeutic agents for the treatment of inflammation and metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003934-25
Application #
8247040
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (02))
Program Officer
Hillery, Paul
Project Start
1985-07-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
25
Fiscal Year
2012
Total Cost
$325,293
Indirect Cost
$56,377
Name
University of North Carolina Greensboro
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
616152567
City
Greensboro
State
NC
Country
United States
Zip Code
27402
Shore, Derek M; Baillie, Gemma L; Hurst, Dow H et al. (2014) Allosteric modulation of a cannabinoid G protein-coupled receptor: binding site elucidation and relationship to G protein signaling. J Biol Chem 289:5828-45
Vallée, Monique; Vitiello, Sergio; Bellocchio, Luigi et al. (2014) Pregnenolone can protect the brain from cannabis intoxication. Science 343:94-8
Lucchesi, Valentina; Hurst, Dow P; Shore, Derek M et al. (2014) CB2-selective cannabinoid receptor ligands: synthesis, pharmacological evaluation, and molecular modeling investigation of 1,8-Naphthyridin-2(1H)-one-3-carboxamides. J Med Chem 57:8777-91
Kimura, Tomohiro; Vukoti, Krishna; Lynch, Diane L et al. (2014) Global fold of human cannabinoid type 2 receptor probed by solid-state 13C-, 15N-MAS NMR and molecular dynamics simulations. Proteins 82:452-65
Kotsikorou, Evangelia; Navas 3rd, Frank; Roche, Michael J et al. (2013) The importance of hydrogen bonding and aromatic stacking to the affinity and efficacy of cannabinoid receptor CB2 antagonist, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carbox J Med Chem 56:6593-612
Baillie, Gemma L; Horswill, James G; Anavi-Goffer, Sharon et al. (2013) CB(1) receptor allosteric modulators display both agonist and signaling pathway specificity. Mol Pharmacol 83:322-38
Marcu, Jahan; Shore, Derek M; Kapur, Ankur et al. (2013) Novel insights into CB1 cannabinoid receptor signaling: a key interaction identified between the extracellular-3 loop and transmembrane helix 2. J Pharmacol Exp Ther 345:189-97
Kotsikorou, Evangelia; Lynch, Diane L; Abood, Mary E et al. (2011) Lipid bilayer molecular dynamics study of lipid-derived agonists of the putative cannabinoid receptor, GPR55. Chem Phys Lipids 164:131-43
Sitkoff, Doree F; Lee, Ning; Ellsworth, Bruce A et al. (2011) Cannabinoid CB(1) receptor ligand binding and function examined through mutagenesis studies of F200 and S383. Eur J Pharmacol 651:9-17
Reggio, Patricia H (2010) Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown. Curr Med Chem 17:1468-86

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