Central nervous system (CNS) responses to delta-9-tetrahydrocannabinol (delta-9-THC) in Cannabis sativa and synthetic cannabimimetic drugs include the therapeutically beneficial effects of analgesia, attenuation of the nausea and vomiting in cancer chemotherapy, appetite stimulation in wasting syndromes, and reduction of intestinal motility. Untoward side effects accompanying these therapeutic responses include alterations in cognition and memory, dysphoria/euphoria, and sedation. Potential therapeutic applications can be found for both CB1 receptor agonist and inverse agonist ligands. It is expected that the CB2 receptor will play a major role in therapeutic manipulation of the immune response. In order to develop therapeutic agents that exhibit selectivity for one subtype over another, it is necessary to understand how agonist ligands interact with the CB1 and CB2 receptors to bind with high affinity and evoke a response. The proposed studies directly examine this interaction, and define mechanisms for inverse agonists that can reverse the effects of active precoupled receptors. Computer-Aided Drug Design (CADD) approaches will be applied (1) to elucidate the structural prerequisites for binding and activity of ligands for the CB1 and CB2 cannabinoid receptors, and (2) to design potent and selective ligands for these receptors.
The specific aims are to test the following hypotheses: 1. CB1 cannabinoid receptor agonists of multiple structural classes (cannabinoid, aminoalkylindole (AAI), and eicosanoid) can bind to common pharmacophoric sites in the CB1 receptor to evoke a response. 2. Agonist ligands of multiple structural classes (cannabinoid, AAI, and eicosanoid) can bind to common pharmacophoric sites on the CB2 receptor. A subset of these pharmacophoric points will differ from those of the CB1 receptor. 3. CB1 receptor antagonists can compete with cannabinoid agonists for binding interactions with the CB1 receptor but are incompetent to induce a conformational transition in the receptor. 4. A population of CB1 cannabinoid receptors exist in a state that can be stabilized by inverse agonist binding (R or R) Determinants of that conformation can be found from the SAR of inverse agonist ligands.
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