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.
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