ABSTRACT

V. CONCLUSION In conclusion, a number of NMDA receptor antagonists remain in clinical trials of which aptiganel (CNS 1102, cerestat), currently in phase Ill, is the most advanced. Aptiganel is a classical open channel blocker and, as such, exhibits the expected mechanism-related side effects in humans (146). However, it may be that its long-term therapeutic benefits outweigh any relatively short-term side effects, thus enabling its use clinically. The future of redox compounds such as nitroglycerin awaits confirmation of their neuroprotective ability in animal models as well as further evidence of their applicability in the absence of cardiovascular complications. Two highly selective NR2B selective antagonists have recently been described: Ro 25-6981, which exhibits a >6000-fold increased affinity for heteromeric NMDAR1/NR2B receptors relative to NMDAR1/NR2A receptors expressed in Xenopus oocytes (147), and CP-101,606 (148). Importantly, Ro 25-6981 (and probably also CP-101,606) appears to share the activitydependent mechanism of antagonism exhibited by ifenprodil (147) and is neuroprotective in animal models of cerebral ischemia at doses that are without untoward CNS side effects (149). Together with the further development of such NR2B selective compounds, another future direction in NMDA receptor antagonists might be the development of NR2A selective compounds. To date no compounds significantly selective for NR2Acontaining receptors have been described but NR2A-subunit knockout mice do not show severe behavioral abnormalities, suggesting that NR2A selective antagonists may not produce too deleterious side effects (150).