SBIR-STTR Award

Neuronal damage in ischemia is initiated by excessive release of glutamate from brain nerve terminals. We have discovered, using novel rapid kinetic methodology developed in our laboratory, that certain substituted guanidines and related compounds are antagonists of calcium-dependent release of glutamate and dopamine from brain nerve terminals. One of these exhibits selective block of glutamate release. Such compounds, which we hypothesize act as antagonists of presynaptic calcium-channels, may be employed as drugs to limit ischemic brain damage in stroke and traumatic brain injury patients. Our goal is to identify and synthesize additional substituted guanidine derivatives of improved potency and specificity for blockade of neurotransmitter release. To that end, we will employ molecular modeling tools and quantitative structure activity relationship analysis. Their mechanism of action and selectivity for antagonism of presynaptic calcium channels will be defined by electrophysiological, radioisotopic flux, and radioligand binding techniques. They will be tested for neuroprotective efficacy in animal models of stroke. Our preliminary in vivo studies have demonstrated neuroprotection by substituted guanidines which block neurotransmitter release.Awardee's statement of the potential commercial applications of the research:The worldwide market for neuroprotective drugs is estimated to be several billion dollars annually. Pharmacotherapies for stroke currently subject to clinical trials focus on NMDA receptor blockers whose use may be limited due to neurotoxicity and calcium antagonists with cardiovascular side effects. It is hoped that our studies may lead to novel drugs with higher efficacy/safety ratios.National Institute of Neurological Disorders and Stroke (NINDS)

Brain damage in stroke and in cardiac arrest results from an inadequate supply of blood to the brain, termed brain ischemia. Brain ischemia depletes the energy stores of affected brain regions and causes the excessive release of glutamate and other neurotransmitters from metabolically compromised nerve terminals. Our goal is to discover synthetic, selective antagonists of the ion channels controlling the release of glutamate and other neurotransmitters. Such compounds may be employed as drugs to limit brain damage in focal ischemia (stroke) and global ischemia (resulting from cardiac arrest or complications of cardiac surgery). Using novel drug discovery methodology based on a proprietary method for monitoring neurotransmitter release from brain nerve terminals, we have developed a novel compound series of synthetic glutamate release blockers, members of which are highly neuroprotective in an animal model of brain ischemia. During Phase II, we hope to incorporate rational drug design strategies resulting from knowledge on the structure of the site of interaction of these neuroprotective compounds with its ion channel targets. Candidates for drug development are likely to emerge from the Phase II project period, and selection of such candidates is the central goal of the project.Awardee's statement of the potential commercial applications of the research: The worldwide market for neuroprotective drugs is estimated to be several billion dollars annually. Pharmacotherapies for stroke currently subject to clinical trials focus on NMDA receptor blockers whose use may be limited due to neurotoxicity, and calcium antagonists with cardiovascular side effects. It is hoped that our studies may lead to novel drugs with higher efficacy/safety ratios.National Institute of Neurological Disorders and Stroke (NINDS)