The overall goal of these studies is the computer aided discovery of novel benzodiazepine receptor (BDZR) ligands for attenuating cognitive dysfunction associated with senile dementia. Concern about convulsive potential is a long-standing impediment to their optimum utilization in cognitive enhancing therapies. The design strategy proposed here increases the likelihood that ligands identified in this study will have better separation between convulsive properties and attenuation of contextual memory dysfunction. Lead compounds, identified with the first generation 3D pharmacophore, will be screened for BDZR binding activity, sedative and convulsive properties, and evaluated for ability to attenuate cognitive impairment in a simple model of cognitive dysfunction. Two useful outcomes will result from this Phase I SBIR: l) First generation novel BDZR compounds with significant inverse agonist properties at the contextual memory endpoint lacking convulsant activity 2) Second generation lead compounds identified on the basis of a refined 3D pharmacophore ready for future assessment. Hence, both sets of compounds have potential for Phase II testing as memory enhancers in cognitive disorders. Given the limited clinical success of currently available therapeutic agents the emergence of an alternative approach for attenuating cognitive dysfunction associated with senile dementia is likely to have a significant impact on treatment.
At present, there has been only limited success from current efforts to develop pharmacological strategies for the treatment of cognitive disorders. These strategies have focused on the drug-induced increase in the activity of cholinergic neurons by the use of muscarinic agonists and cholinesterase inhibitors. A possible reason for this limited success is that an effective strategy is likely to require both augmenting the function of the surviving neuronal processes and preserving the highly complex transmission patterns typical for cortical ACh neural pathways. A promising alternative approach, which meets these requirements, supported by substantial reported evidence and by our prior studies, is a strategy that attenuates senile dementia related cognitive dysfunction by regulating ACh neural pathways via the modulation of GABAergic inhibitory pathways. This alternative approach to the treatment of cognitive disorders has an increased probability of success and hence a large commercial potential.
