Structure-based discovery of positive allosteric modulators of the alpha7 nicotinic acetylcholine receptor as cognition enhancers.

The alpha7 nicotinic acetylcholine receptor (nAChR) has attracted considerable attention as an emerging therapeutic target for the treatment of neurological disorders associated with cognitive dysfunction, such as schizophrenia and Alzheimer's disease. Both of these diseases are associated with a decline in cognitive function for which there remains an unmet medical need. We will employ a structure-based drug discovery approach, which takes advantage of X-ray crystal structures of compounds in complex with the alpha7 nAChR mimic, alpha7-AChBP (acetylcholine binding protein). Additionally, we will functionally characterize these compounds with Surface Plasmon Resonance (SPR) and electrophysiological recordings on the human alpha7 nAChR. Using this multidisciplinary state-of-the-art approach we will develop novel positive allosteric modulators (PAMs) for the alpha7 nAChR, which enhance the effect of the endogenous neurotransmitter acetylcholine, thereby restoring cognition, and without perturbing the normal fluctuations in cholinergic signaling. Our goal is to file a patent protecting these novel PAMs and to negotiate a license agreement with a pharmaceutical partner f or further development.

Keywords:cognition enhancers

Disciplines:Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing