The purpose of the proposed project is to develop a new muscarinic agonist for the treatment of schizophrenia. Compounds that activate M1 and M4 muscarinic receptors are expected to be particularly useful in treating memory and cognitive deficits, as well as the behavioral disturbances associated with schizophrenia. Recent studies at the University of Toledo have identified a novel class of compounds with strong activity at both M1 and M4 receptors. The compounds bind to muscarinic receptors in a unique manner that limits side effects associated with activation of other receptors. Of these compounds, CDD-0304 displays the highest activity at M1 receptors, which play an important role in memory and cognitive function, and the lowest activity at M3 receptors, which mediate a variety of unwanted actions, including salivation and diarrhea. The studies outlined here will expand upon previous work and initiate the commercialization of the technology that is owned by the University and licensed to Cognitive Pharmaceuticals Ltd. Initially, the work will focus on synthesizing analogs of CDD-0304 to optimize activity at M1 and M4 receptors, while limiting activity at M2 and M3 receptors. Compounds will be evaluated for receptor binding properties and agonist activity at muscarinic receptor subtypes utilizing cells expressing the individual human muscarinic receptor subtypes. For compounds that bind selectively, pharmacological screens will evaluate side effect profiles, while ex vivo binding assays and drug distribution studies will examine CNS penetration. For compounds that show low side-effect profiles and penetrate the CNS, antipsychotic activity will examined by measuring the ability of CDD-0304 and analogs to modulate the impairment of pre-pulse inhibition associated with administration of apomorphine, a dopamine agonist. The ability of compounds to enhance cognitive function also will be evaluated. The metabolism of compounds that are efficacious in the animal model will be examined in preliminary fashion. Together, the proposed studies will identify a lead compound to move into full preclinical development for the treatment of cognitive deficits and other symptoms associated with schizophrenia. ? ? ?
