The synthesis of compounds derived from SR141716A, a potent antagonist of delta9-THC and cannabimimetics, may lead to the identification of unique antagonists, inverse agonists, as well as a new structural class of agonists. These efforts would further our understanding of cannabinoid structure-activity relationships, facilitate our understanding of the cannabinoid neurochemical system and provide biochemical tools and potential medicinal agents relevant to drug abuse and to brain function. The development of specific antagonists for the CB2 receptor would also contribute to our understanding of the structural requirements for selective interactions of both agonists and antagonists with cannabinoid receptor subtypes.
The specific aims of the proposed research are based on results of preliminary studies showing that analogs of SR141716A could be synthesized with unique characteristics: high affinity for cannabinoid receptors, and affinity for a population of neuronal cannabinoid binding sites that is distinguishable from the population to which cannabinoid agonists bind. These analogs' structure-activity relationships are consistent with a pharmacophoric overlay of SR141716A with delta9-THC and other cannabinoids which identifies regions of similarity and of disparity between Cannabinoid agonists and antagonists and serves as a paradigm for further examining the structural requirements of these classes of compounds. Compounds designed from this molecular overlay with delta9-THC include those probing the side chain structural analogy, analogs probing the putative antagonist conferring interaction, analogs of the pyran oxygen interaction and pyrazole / phenol correspondence analogs. Pharmacological assays to evaluate these analogs will include a comparative receptor binding assay with [3H]SR141716A and [3H]CP-55,940 in rat brain preparations and transfected cell lines to establish each compounds affinity and selectivity. An accepted signal transduction assay using [35S]GTP-gamma-S will be performed on selected compounds to characterize their efficacy. Analogs of highest interest will also be tested in isolated tissues (mouse vas deferens and guinea pig ileum) and in vivo in the mouse and rat to identify compounds with in situ and in vivo activity. Upon completion of pharmacological profiling, the research program is intended to continue to test and evolve a computational model of cannabinoid structure-activity relationships in an iterative fashion.
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