The objectives of this project are to study the cannabinoid receptor- effector interactions at cellular and molecular levels in an effort to define the requirements for agonist and antagonist binding and production of a response. The first site of action of a drug is at the level of the receptor at the cell surface. If the ligand is an agonist, this ligand/receptor interaction will result in the induction or stabilization of a conformation of the receptor protein such that a productive interaction with an effector protein can take place. The adenylate cydase enzyme complex is the effector system coupled to the cannabinoid receptor. The inhibition of adenylate cyclase by cannabinoid drugs woldd modify the neuronal response as a result of a change in the phosphorylation state of critical regulatory enzymes and proteins. Subsequent alterations in the behavior of the neuron are manifest in the intact animal as one or more of the typical responses observed after administration of a cannabimimetic drug, e.g. cognitive and memory dysfunction, analgesia, changes in endocrine functions, or hypothermia and hypokinesia (immobility) observed in rodents.
The specific aims are as follows: 1: To study the Structure-Activity Relationships of a series of cannabinoid compounds for their ability to bind to the cannabinoid receptor and to evoke the response of inhibition of adenylate cyclase. 2: To examine three irreversibly binding ligands for their actions at the cannabinoid receptor including binding and ability to evoke a persistenit response or an antagonistic action. 3: To evaluate three potential Positron Emission Tomography (PET) scanning ligands for their actions at the camabinoid receptor. The knowledge obtained from this study is essential 1) for the rational design of new therapeutic-entities, such as cannabinoid analgetic agents, 2) for the design and synthesis of analogs having agonist or antagonist activity at the cannabinoid receptor, and 3) to provide the basis for defining cannabinoid receptor subtypes which may ultimately be shown to be responsible for certain of the multiple biological effects of cannabinoid drugs.
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