As the U.S. population ages, the incidence of Alzheimer s disease will rise dramatically. Senile dementia of the Alzheimer's type (SDAT) arises from progressive failure of the cholinergic system, impairing memory and hypofunction. These approaches tend to elicit direct postsynaptic stimulation, causing constant, tonic neuronal activity unfavorable to normal cognitive processing, which is a serious drawback. An alternative but largely unexploited strategy for ameliorating cogninve decline associated with cholinergic hypofunction is to use one of the brain's own internal control systems, GABAergic inhibitory modulation of cholinergic inputs, to augment the impact of cholinergic excitation in the hippocampus. Using an interdisciplinary approach, we propose to demonstrate that compounds developed to specifically interact with a subset of GABA-A receptors containing the alpha5 subunit, found almost exclusively on pyramidal cells of the hippocampus, can be designed to dampen GABA-mediated CI- passage into the neuron. This would effectively counteract contextual memory deficits caused by cholinergic hypofunction. We intend to achieve this through the application of a unique computational tool we have developed in which both behavioral data and in vitro binding and activation data are used to build models (known as 3D pharmacophores) that reflects the essential chemical features inherent to BDZR ligands crucial to enhancing contextual memory. The previously developed 3D recognition pharmacophore has subsequently aided us in identifying the alpha 5 subunit of the GABAA receptor as a key element in GABAergic influence on contextual memory. The overall goal of this Phase I SBIR proposal is to use the information contained within contextual memory 3D pharmacophores (both recognition and activation) to direct the synthesis of candidate compounds that specifically, bind to the benzodiazepine binding site on GABA-A receptors containing the as subunit and cause a strong reduction in GABA-mediated Cl- currents, thereby optimal enhancing contextual memory function while simultaneously minimizing undesirable side-effects. The success of this proposal will demonstrate the viability of developing highly efficacious, activation-specific BDZR ligands capable of alleviating contextual memory deficits attributed to cholinergic hypofunction. This will lay the groundwork for pursuing the most promising lead compounds in a Phase II application aimed at addressing the serious problem of cognitive decline observed in aging and SDAT.
| Harris, Danni; Clayton, Terry; Cook, James et al. (2008) Selective influence on contextual memory: physiochemical properties associated with selectivity of benzodiazepine ligands at GABAA receptors containing the alpha5 subunit. J Med Chem 51:3788-803 |
