The long-term goal of this research project is to elucidate the basis for the actions of the cannabinoids 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. This detailed understanding of cannabinoid action will first be sought in the development of a pharmacophore for the aminoalkylindoles (AAIs) and in an exploration of the pharmacophore requirements of the anandamides (endogenous cannabinoids). The information we expect to gain from these studies will complement the pharmacophore we have developed previously for the classical and non-classical cannabinoids. Along with a variety of computational approaches these data will be used to complete a three dimensional model of the CB1 receptor currently under construction. Computational simulations of the time-dependent structural properties of the receptor and its complexes with ligands also will be considered in light of developments in the field of G Protein-Coupled Receptor (GPCR) modeling. This approach is very attractive because it allows one to probe not only recognition but also activation. Our work will be aided and supplemented at each step of pharmacophore and receptor model development by collaboration with experimental medicinal chemists, pharmacologists and molecular biologists. The results of these proposed studies should contribute to an understanding of the actions of the cannabinoids at a molecular level.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003934-11
Application #
2668110
Study Section
Special Emphasis Panel (SRCD (11))
Program Officer
Hillery, Paul
Project Start
1985-07-01
Project End
1999-02-28
Budget Start
1998-03-01
Budget End
1999-02-28
Support Year
11
Fiscal Year
1998
Total Cost
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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