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.
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