NMDAR Blocker

Dingledine, R; Traynelis, S

The NMDA receptor (NMDAR), a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function. A substantial body of data supports the expectation that a NMDAR antagonist would confer neuroprotection after neural insults such as ischemia, as well as offer relief from neuropathic pain and psychological disorders such as major depression. Unfortunately, to date, most NMDAR antagonists that reached clinical development have failed as a result of unacceptable side effects at the dose levels required. Neurop Inc. is developing two classes of NR2B-specific NMDAR antagonists with promising therapeutic profiles, in-licensed from Emory, for CNS related conditions. In conjunction with Bristol-Myers Squibb, Neurop is developing a class of NR2B-specific NMDAR antagonists with high efficacy and low toxicity for treatment of major depression and neuropathic pain. Because these compounds bind only NMDA receptors containing the NR2B subunit as noncompetitive, allosteric antagonists, they offers regional selectivity and preserve some necessary NMDA receptor activity. Separately, Neurop is developing certain NR2B-specific NMDAR antagonists that are pH sensitive for subarachnoid hemorrhage and other ischemic conditions. These compounds are minimally active in healthy, normal tissue, but in areas in which ischemia or pathological activation have reduced the extracellular pH, the drugs become potent, effective NMDAR antagonists.