NMDA antagonist

Details NMDA antagonist NMDA antagonist

1999-08-23

2001-08-14

Krass, Frederick (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated inorganic nonactive ingredient or elemental...

C424S600000, C514S816000, C514S959000, C514S220000, C514S759000, C514S731000, C514S812000

Reexamination Certificate

active

06274633

ABSTRACT:

CROSS-REFERENCES TO RELATED APPLICATIONS
This application claims priority benefit under Title 35, United States Code §119 of United Kingdom application number 9917822.0 filed Jul 22, 1999.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
Not Applicable
BACKGROUND OF THE INVENTION
The present invention relates to a method of modulating the activity of NMDA receptors in a mammal. In particular, the invention relates to a new NMDA antagonist, and its use in the treatment of conditions associated with NMDA receptor activity.
The NMDA (N-methyl-D-aspartate) receptor is a major subclass of glutamate receptor and glutamate is believed to be the most important excitatory neurotransmitter in the mammalian central nervous system. Importantly, activation of the NMDA receptor has been shown to be the central event which leads to excitotoxicity and neuronal death in many disease states, as well as a result of hypoxia and ischaemia following head trauma, stroke and following cardiac arrest.
It is known in the art that the NMDA receptor plays a major role in the synaptic plasticity which underlies many higher cognitive functions, such as memory and learning, as well as in certain nociceptive pathways and in the perception of pain (Collingridge et al, The NMDA Receptor, Oxford University Press, 1994). In addition, certain properties of NMDA receptors suggest that they may be involved in the information-processing in the brain which underlies consciousness itself.
NMDA receptor antagonists are therapeutically valuable for a number of reasons, such as the following three specific reasons. Firstly, NMDA receptor antagonists confer profound analgesia, a highly desirable component of general anaesthesia and sedation. Secondly, NMDA receptor antagonists are neuroprotective under many clinically relevant circumstances (including ischemia, brain trauma, neuropathic pain states, and certain types of convulsions). Thirdly, NMDA receptor antagonists confer a valuable degree of amnesia.
However, it is clear from the prior art that there are a number of drawbacks associated with current NMDA receptor antagonists. These include the production of involuntary movements, stimulation of the sympathetic nervous system, induction of neurotoxicity at high doses (which is pertinent since NMDA receptor antagonists have low potencies as general anaesthetics), depression of the myocardium, and proconvulsions in some epileptogenic paradigms e.g., “kindling” (Wlaz P et al, Eur. J. Neurosci. 1994; 6:1710-1719). In particular, there have been considerable difficulties in developing new NMDA receptor antagonists that are able to cross the blood-brain barrier. This factor has also limited the therapeutic applications of many known NMDA antagonists.
The present invention thus seeks to provide an improved NMDA receptor antagonist for general pharmaceutical use which can readily diffuse across the blood brain barrier.
BRIEF SUMMARY OF THE INVENTION
This invention relates to the use of xenon as an NMDA antagonist. Encompassed by the invention are methods of treating mammals by modulating the activity of an NMDA receptor, and methods of modulting the activity of an NMDA receptor by administering to a mammal a therapeutically effective amount of xenon. Various aspects of the invention are presented in the following description and accompanying claims.


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