The purpose of the proposed research is to develop new approaches for designing compounds to treat neurological disorders. Changes in cholinergic activity have been implicated in a variety of pathological conditions including Alzheimer's disease and schizophrenia. Muscarinic agonists might be helpful in restoring the chemical imbalances in cholinergic activity associated with neurological disorders. Unfortunately, the development of new therapies is hindered by the propensity for muscarinic agonists to produce unwanted side effects due to activation of multiple receptor subtypes. An integrated approach to drug development is proposed whereby information from molecular biological and computational chemical studies is used in the design and development of selective muscarinic agonists. Chimeric receptors will be generated to help determine where molecules bind to muscarinic receptor subtypes. Molecular models of muscarinic receptors will be created in order to understand how agonists stabilize the active form of the receptor. Existing ligands will be docked into the muscarinic receptor model to verify interactions discovered in studies of chimeric receptors and to identify amino acid residues that represent binding sites for functional groups on selective ligands. New compounds will be designed and synthesized to take advantage of the information derived from the molecular biological and computational chemical studies. Compounds will be characterized for receptor binding properties and functional activities in cell lines expressing muscarinic receptor subtypes. Muscarinic agonists that display high activity and selectivity will be examined further in functional assays for enhancement of memory function and antipsychotic activity in animal models of Alzheimer's disease and schizophrenia, respectively. The studies outlined here will provide new approaches for the treatment of neurological disorders, including Alzheimer's disease and schizophrenia.
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