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 three emphases: ligand-receptor recognition, ligand-induced receptor activation/inactivation and agonist-independent activation of the CB receptors. In ligand-receptor recognition studies, we will focus on required recognition elements for ligand interaction at the CB receptors. We will infer information about the CB receptors and/or modes of binding interactions at these receptors from a correlation between experimentally determined receptor affinities and biological activities and the structural and electronic features of a series of cannabinoid ligands. At each step, our work will be aided and supplemented by collaboration with experimental medicinal chemists and pharmacologists. Compounds proposed for synthesis here have been designed to test specific hypotheses that have emerged during the current grant period. Pharmacological results from evaluation of these new compounds will be used to refine the pharmacophores we construct. These pharmacophores then will be tested in receptor mutation studies. In receptor activation studies, we will analyze the interaction of CB ligands with 3D models of the CB1 and CB2 receptors that we have developed and refined. These studies will elucidate required recognition elements and probe consequences of ligand binding. At each step, this work will be aided and supplemented by collaboration with experimental pharmacologists and molecularbiologists. In agonist-independent activation studies of the CB receptors, we will probe our models of the CBreceptors to identify interactions between residues in key regions or interactions between the receptor and its environment that may lead to agonist independent activation of the CB receptors. At each step, this work will be aided and supplemented by collaboration with experimental pharmacologists and molecular biologists. Information about cannabinoid receptor structure and binding modes of ligands will aid infundamental structure-function studies of this important class of receptors and will also aid in the design of improved therapeutic agents based on the cannabinoids.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA003934-16
Application #
6630677
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Hillery, Paul
Project Start
1985-07-01
Project End
2004-07-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
16
Fiscal Year
2003
Total Cost
$233,117
Indirect Cost
Name
Kennesaw State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
627758923
City
Kennesaw
State
GA
Country
United States
Zip Code
30144
Morales, Paula; Isawi, Israa; Reggio, Patricia H (2018) Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12. Drug Metab Rev 50:74-93
Ragusa, Giulio; Bencivenni, Serena; Morales, Paula et al. (2018) Synthesis, Pharmacological Evaluation, and Docking Studies of Novel Pyridazinone-Based Cannabinoid Receptor Type?2 Ligands. ChemMedChem 13:1102-1114
Morales, Paula; Reggio, Patricia H; Jagerovic, Nadine (2017) An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol. Front Pharmacol 8:422
Morales, Paula; Hurst, Dow P; Reggio, Patricia H (2017) Methods for the Development of In Silico GPCR Models. Methods Enzymol 593:405-448
Lynch, Diane L; Hurst, Dow P; Shore, Derek M et al. (2017) Molecular Dynamics Methodologies for Probing Cannabinoid Ligand/Receptor Interaction. Methods Enzymol 593:449-490
Morales, Paula; Hurst, Dow P; Reggio, Patricia H (2017) Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod 103:103-131
Seltzman, Herbert H; Maitra, Rangan; Bortoff, Katharine et al. (2017) Metabolic Profiling of CB1 Neutral Antagonists. Methods Enzymol 593:199-215
Carter, Patrick M; Cook, Lawrence J; Macy, Michelle L et al. (2017) Individual and Neighborhood Characteristics of Children Seeking Emergency Department Care for Firearm Injuries Within the PECARN Network. Acad Emerg Med 24:803-813
Laprairie, Robert B; Kulkarni, Abhijit R; Kulkarni, Pushkar M et al. (2016) Mapping Cannabinoid 1 Receptor Allosteric Site(s): Critical Molecular Determinant and Signaling Profile of GAT100, a Novel, Potent, and Irreversibly Binding Probe. ACS Chem Neurosci 7:776-98
Morales, Paula; Gómez-Cañas, María; Navarro, Gemma et al. (2016) Chromenopyrazole, a Versatile Cannabinoid Scaffold with in Vivo Activity in a Model of Multiple Sclerosis. J Med Chem 59:6753-6771

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