This is a competitive renewal request for a project (DA-3801) aimed at better understanding the molecular basis of action of cannabimimetic agents (CBMMs). This information will be useful for the design of novel therapeutic CBMMs including analgesics for AIDs wasting syndrome and as immunomodulatory agents. The pharmacological effects of cannabimimetic agents are determined by their abilities to a) interact with the cannabinoid receptors, b) perturb cellular membranes, and c) to cross the blood brain barrier (BBB). This project will seek to correlate the molecular properties of CBMMs with each of the above three aspects of their activity (a,b,c). To this effect we shall study the conformational properties of CBMMs interactions with both model and biological membranes, and their interactions with native cannabinoid receptors to obtain direct information on the structures of the cannabinoid receptor sites. During the previous funding period, our work has focused largely on the classical and non-classical cannabinoids (CCs and NCCs) and the molecular requirements for agonist activity at the CB1 receptor. We now propose to expand the scope of this work by including a) a more comprehensive group of CBMM amino alkylindole analogs (AAIs), b) arachidonylethanolamide (anandamide) and its analogs (AEAs), and c) newly discovered cannabinoid antagonists. Along with the CB1 receptor, our studies will also include the newly discovered CB2 and the CB1 variant CB1a. The project includes representative analogs from each of the CBMM classes. Our studies will seek to distinguish among i) the receptor-related CBMM effects from those due to the interactions with cellular membranes by seeking to develop correlations between CBMM structures and each of the two effects, ii) structural requirements for interactions with CB1, CB2 and CB1a receptors, and iii) structure requirements for agonist and antagonist CBMM activity. Correlations will also be developed between CBMM structure and the drug's ability to cross the blood brain barrier (BBB). Our findings will be correlated with already available biochemical results and supplemented with additional biochemical and pharmacological data including receptor binding, Gi protein coupling, immuno-modulatory and antinociceptive effects and ability to cross the BBB obtained either from our laboratory or collaborators.
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