MonthlyUpdate—Central & Peripheral Nervous Systems: Pharmacotherapeutic Potential for Compounds Acting at NMDA Receptors: Update 1995

Abstract

The exciting developments of the past year occurring since our last comprehensive review of NMDA receptor pharmacological agents as drugs [1], not yet appearing in the refereed literature, involve the use of NMDA antagonists in stroke and traumatic brain injury. A year ago, there seemed to be a three way tie in the race for effective ‘brain-attack’ (emergency anti-stroke rescue therapy) and traumatic brain injury therapy between the anti-oxidant tirilazad (Upjohn), the NMDA-antagonist selfotel (Ciba, CGS 19755), and the NMDA-antagonist eliprodil (Synthelabo/Searle/Lorex, SL 82.0715). Unexpected side-effects severely retarded the progress of tirilazad, and the ‘dark horse’ glutamate-release blocker lubeluzole (Janssen) suddenly burst into, possibly, the leading position in this race, with selfotel and eliprodil still jockeying effectively as they move into Phase III trials in stroke. Some attention has also been focused on trials involving drug combinations. Although theoretically this would offer the advantage of multiple ‘sites’ of attack with different agents while decreasing the dose of any individual agent, there appears to be some evidence to suggest respiratory depression [2, 3]. A very important emerging recognition is that glutamate acting on neuronal receptors may not always be of neuronal origin, particularly in pathological conditions. Astrocytes are capable of releasing relevant amounts of glutamate to affect neurones [4], and, under ischaemic and traumatic brain injury conditions, some glutamate (and other amino acids) may be derived from breaches in the blood-brain barrier. Among many other excellent reviews, one outstanding comprehensive review peering into the potential clinical future of excitatory amino acids' role in neurological disorders has appeared [5], and there are several outstanding comprehensive reviews on the basic and molecular aspects of NMDA receptors [6–8]. Discerning discussions of the second messenger pathways involved in glutamate receptor stimulation (a very complex subject open to much more speculation and debate) have also appeared [9–12]. The potential for using agonists of the NMDA receptor complex as cognitive enhancers has been reviewed separately [13].