Development of a Selective Muscarinic Agonist for the Treatment of Schizophrenia

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to develop selective muscarinic agonists for the treatment of psychosis and cognitive dysfunction associated with schizophrenia. Cognitive deficits, including impaired memory function, are strongly linked to the long- term disabilities found in patients with schizophrenia. Amelioration of cognitive deficits associated with schizophrenia represents an important clinical target for drug development that has not been addressed by the pharmaceutical industry. Previous studies definitively identified CDD-0304 as a lead compound for the treatment of schizophrenia. Continuation of analog synthesis efforts and the pharmacological evaluation of CDD 0304 derivatives are proposed in this application, with an emphasis on identifying a back-up compound. Compounds within the series with particular receptor selectivity, CNS penetration, and efficacy in animal models of schizophrenia and cognitive function will be evaluated. In addition, pharmacokinetic properties and the safety of CDD-0304 and related compounds will be assessed. Specific aims include: 1) Synthesis and pharmacological evaluation of novel muscarinic agonists, 2) In vivo CNS penetration, functional activity, and selectivity, 3) Scale-up and analytical chemistry and 4) Further determination of ADME and toxic properties of CDD- 0304 and analogs. These studies, with some additional investment, will complete the preclinical package necessary to file an IND application with the Food and Drug Administration for a novel muscarinic agonist with potential utility in the treatment of schizophrenia. The overall goal of the proposed research is to develop new compounds for the treatment of psychosis and cognitive dysfunction associated with schizophrenia. Cognitive deficits, including impaired memory function, are strongly linked to the long- term disabilities found in patients with schizophrenia. Treatment of cognitive deficits associated with schizophrenia represents an important clinical target for drug development that has not been addressed by the pharmaceutical industry. The studies outlined in the proposal will help provide the data necessary for advancing a compound to clinical testing.