Alterations in the functional activity and/or number of serotonin2 (5-HT2) and/or serotonin1C (5-HT-1c) receptors have been implicated in the pathophysiology of a large number of mental illnesses including obsessive- compulsive disorder, schizophrenia, depression, anxiety, dysthymia, suicide, aggression and eating disorders. Additionally, a number of psycho- and neuropharmacologic agents including antidepressants (mianserin, amitriptyline, imipramine), antipsychotic drugs (loxapine, clozapine), hallucinogens (lysergic acid diethylamide) and anti-dysthymic agents (ritanserin) bind to 5-HT2 and 5-HT-1c receptors. Determining the precise roles the 5-HT2 and 5-HT-1c receptors have in mediating the effects of these agents is difficult because no truly subtype selective agents are currently available. Insights we gain in understanding how drugs bind to each of these receptors should enhance our ability to design novel receptor-specific agents which can be used to treat mental illnesses. This proposal will determine how agonists and antagonists bind to 5-HT2 and 5-HT-1c receptors. We will utilize the techniques of molecular biology and receptor pharmacology to identify specific amino acids essential for specifying the ligand binding domains of each receptor. We are utilizing four major techniques. (1) chimeric protein construction (2) site directed mutagenesis, (3) molecular modelling and (4) structural biochemical measurements. Our strategy is to test three-dimensional molecular models of 5- HT2 and 5- HT-1c receptor-ligand interactions using a combination of molecular biological and structural-biochemical techniques. We will also take advantage of unique mutations we have produced to probe the molecular details responsible for hallucinogen- induced alterations of serotonin receptors in vitro. These findings will be useful for the design and synthesis of new medications to treat psychiatric diseases.
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