Substantial evidence indicates that excitatory amino acid (EAA) neurotransmission plays a role in the pathophysiology of epilepsy, neurodegenerative disorders and the neuronal damage that occurs following hypoxic or ischemic CNS insult. Of the three recognized EAA recognized EAA receptor subtypes (quisqualate, kainate and N- methyl-D-aspartate: NMDA), animal experiments clearly indicate that NMDA antagonists may provide an effective prophylactic, symptomatic or ameliorative approach to treatment of these disorders. Subclasses of NMDA receptors are thought to exist in brain. Furthermore, some NMDA receptors may be linked to the site of action of dissociative anesthetics since agents including phencyclidine (PCP) ketamine, dextrorphan, dexoxadrol and MK801 noncompetitively antagonize NMDA receptor-mediated responses. Notably, many of these compounds are potent anti-convulsants and have been shown to prevent ischemic and hypoxic damage to brain. Known competitive NMDA antagonists are polar compounds which penetrate poorly to brain. Conversely, noncompetitive antagonists are highly lipophilic, but often elicit PCP-like psychotomimetic responses making them unsuitable for chronic administration. Recent evidence suggests it may be possible to separate the beneficial properties from the psychotomimetic side-effect liabilities of noncompetitive antagonists. Building upon a unique series of compounds already identified by NOVA to interact with PCP recognition sites in brain, the current Phase 1 proposal seeks funds for further medicinal chemical efforts and advanced evaluation of the behavioral effects of this series. Testing will include determination of the anticonvulsant and neuroprotective properties of these agents as well as the potential side-effect liabilities using drug discrimination paradigms. Compounds identified as having the desired pharmacological properties would be further evaluated in a Phase II application as potential IND candidates.
