The long range goals of our work are to elucidate the molecular determinants for cannabinoid psychopharmacological activity and for cannaboid analgesic activity, and to use this knowledge to design new cannaboid analgesics with reduced psychopharmacological liability. To this end, we propose here to refine the templates we have revealed for the molecular basis of cannaboid psychopharmacological activity and for the molecular basis of cannaboid analgesic activity. The theoretical work proposed here will be tested, supplemented, and enhanced by collaborative studies with experimentalists. Hypotheses which have resulted from our theoretical studies form the basis in this application for the synthesis of new analogs and their evaluation in experiments in behavioral and molecular pharmacology. The research plan has been designed to test the following hypotheses: (1) that the discriminative basis of psychopharmacological activity in these compounds is the set of molecular properties conferred by the orientation of the lone pairs of electrons of the phenyl group hydroxyl oxygen and by the orientation of the carbocyclic ring and its C-9 substituent such that they move out of the alpha face of the molecule, and (2) that the basis of analgesic activity in these compounds is the set of molecular properties conferred by the presence and relative location of two negative potential regions in the top half of the cannaboid analgesic molecule and by the orientation of the carbocyclic ring and its C-9 substituent such that they move out of the alpha face of the molecule. To explore these hypotheses and to develop new guides for the design of compounds with discriminant psychopharmacological and analgesic properties, we will examine twenty-seven molecules from disparate structural classes of cannaboids which possess such activity in varying degrees. The theoretical methods employed here permit the accounting for the pharmacological activity/inactivity of cannaboids which are structurally dissimilar, as well as, of cannaboids which are structurally very similar. In order to make possible this analysis of disparate classes of cannaboids, the requirements for each activity are formulated by Molecular Reactivity Characteristics that are independent of atom-to-atom resemblances among subject molecules. Such characteristics include the Molecular Electrostatic Potential and the Receptor Steric map of these compounds calculated in the preferred molecular conformation and in conformations defined by hypotheses on their mode of interaction with specific targets (e.g. receptors). The results of these studies should contribute to an understanding of the actions of the cannabinoids at the molecular level and should provide an invaluable tools for the rational drug design of cannabinoid therapeutic agents with reduced psychoactive liability.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Drug Abuse Biomedical Research Review Committee (DABR)
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Hillery, Paul
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Kennesaw State University
Schools of Arts and Sciences
United States
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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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