NMDA Background
The function of the brain is largely dependent upon the communication between individual nerve cells. In mammals, a single nerve cell communicates with another by releasing chemicals that alter the electrical activity of the receiving cell. These chemicals are known as "neurotransmitters". By far the most abundant excitatory neurotransmitter in the mammalian brain is glutamate. Curiously, this is exactly the same as the taste enhancer commonly used in Asian cooking known as "Umami" or MSG (Mono Sodium Glutamate)! Glutamate changes the activity of the receiving nerve cell by binding to specific proteins on the surface of the nerve cells, known as "receptors". When glutamate binds to such receptors, the flow of positively charged ions, such as sodium, calcium, and potassium, across the membrane of the nerve cell is altered. This different flow of ions is "felt" by the receiving nerve cell as "communication" inducing a certain action of that cell. To improve the specificity of such action, glutamate acts on many different types of receptors and at least 30 different proteins contribute to the heterogeneity of glutamate receptors. A major glutamate receptor family is known as the NMDA receptor family. This rather cumbersome name arises from a glutamate analog "N-methyl-D-aspartate" that was found to activate these receptors selectively.
Apart from their normal physiological communication roles, NMDA receptors are important players in certain diseases such as neuro-degeneration, pathological pain states, and in conditions such as Parkinson's disease and epilepsy. The hypothesis is that when you can block the NMDA function with an "antagonist", this will positively impact the disease. Extensive studies over the last 15 years have indicated a potential role for NMDA receptor antagonists in the treatment of these diseases. However, the clinical development of non-selective antagonists has shown unfavorable side-effects such as hallucinations and effects on movement. In the early 1990's it was found that multiple NMDA receptor subtypes exist which contain different NR2(A-D) subunits. Compounds selectively targeting NR2B subunit-containing receptors are expected to retain many of the beneficial effects of earlier non-selective compounds but have much improved side effect profiles. Such NR2B specific compounds are at the heart of Evotec's NMDA receptor program.
