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.
| Kirk, C J; Reddy, N L; Fischer, J B et al. (1994) In vitro neuroprotection by substituted guanidines with varying affinities for the N-methyl-D-aspartate receptor ionophore and for sigma sites. J Pharmacol Exp Ther 271:1080-5 |
| Reddy, N L; Hu, L Y; Cotter, R E et al. (1994) Synthesis and structure-activity studies of N,N'-diarylguanidine derivatives. N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine: a new, selective noncompetitive NMDA receptor antagonist. J Med Chem 37:260-7 |
