Research Project
3504347
The goal of this project is to provide a treatment for neurological conditions, such as epilepsy, stroke, trauma and a number of neurodegenerative diseases, which involve, or are caused by, excessive excitation of nerve cells by agonist of the NMDA sub-type of glutamate receptors. Experiments performed at Cambridge NeuroScience Research and in collaboration with the Department of Chemistry at the University of Oregon have demonstrated that certain N, N'-disubstituted guanidines: bind to the `PCP receptor' associated with the NMDA- receptor; block the ion-channel of the NMDA-receptor; and, can protect nerve cells from glutamate-induced cell death in both in vitro and in vivo models. In Phase I of this project second generation N,N'-disubstituted guanidines will be synthesized and tested for their ability: a) to inhibit binding to the PCP receptor in rat brain membranes; b) to block NMDA-activated ion-channels on cultured rat brain neurones; c) to prevent the glutamate-induced death of neurons in an in vitro system; and d) to reduced or anoxia/ischaemia-induced neuronal degeneration in animals when administered systemically. Lead neuroprotective compounds will be selected by this screening procedure. Phase II will involve the scale-up synthesis of these compounds and investigations of their: efficacy in further animal models of neurological disorders; toxicity; and, bioavailability.
