The overall goal of this project is to conduct a preliminary exploration of the molecular parameters that will serve to unify Structure Activity Relationships (SAR's) in disparate classes of cannabinoids. In the eighteen month period of the project the methods of theoretical chemistry (quantum chemistry) will be used to go beyond steric considerations that have before prevailed in SAR studies of cannabinoid action. The molecular properties associated with each cannabinoid structure will be examined in order to learn their relation to the pharmacological actions of these compounds. The rank orders of activities of these compounds in specific pharmacological endpoints that have been correlated with the psychopharmacological activity of the cannabinoids will be used to quantitate structure-activity rankings. The hypothesis to be tested is one which emerged from a review of structure-function relationships in these classes of compounds. According to this hypothesis, the basis of activity in the cannabinoids is the set of molecular properties conferred by the lone pairs of electrons of the phenol oxygen and by the orientation of the carbocyclic ring, ring A, with respect to the aromatic ring and its OH substituent. To this end delta-9-THC and nine other cannabinoids will be examined. In order to make possible this analysis of disparate classes of cannabinoids, the requirements for activity will be formulated by Molecular (chemical) Reactivity Characteristics (MRC's) that are independent of atom-to-atom resemblance among cannabinoids. Such characteristics include the molecular electrostatic potential (MEP) and the accessible molecular surface of these compounds calculated in the preferred molecular conformation and in conformations defined by hypotheses on their mode of interaction with a specific target (e.g. a receptor). The MRC's for delta-9-THC will be used as criteria for the psychopharmacological activity of other cannabinoids. The MRC's of other cannabinoids will be compared to those of delta-9-THC in order to provide a profile of the molecular characteristics necessary for cannabinoid activity. By ascertaining the molecular structural and electronic factors which are responsible for activity, we will account for the activity of cannabinoids with dramatically different structures, as well as the activity/inactivity of cannabinoids with subtle structural differences. The results of this study should contribute to an understanding of the actions of the cannabinoids at the molecular level.
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