This compound has displayed significant activity in animal models of epilepsy (maximal
electroshock assay) and stroke (focal ischemia model). In addition, a number of
3-substituted indole-2-carboxylates were shown to be powerful glycine site antagonists.
From these studies, and from related molecular modeling investigations, it became
apparent that the NMDA glycine recognition site possessed a large lipophilic pocket
adjacent to the 3-position of the indole nucleus; reduction of the indole completely
abolished compound affinity for the receptor site.
Compounds targeting the glycine receptors have had mixed success as drug candi-
dates. In terms of drugs developed for epilepsy, felbamate (4.205), active at the NMDA
glycine subsite, is a potent anticonvulsant but has run into toxicity problems, causing
aplastic anemia (suppression of the bone marrow). Drugs targeting the NMDA glycine
site and designed for stroke have had even greater developmental problems. Although
many of these compounds work very well against animal models of stroke, they have
uniformly failed to be of significant value when used in Phase III human trials of the
same disease. This observation calls into question the utility of some of the animal
models of stroke that are currently employed.
4.9 EXCITATORY AMINO ACID
NEUROTRANSMITTERS: GLUTAMATEGlutamate (4.206) and aspartate (4.207) have long been known as excitatory transmit-
ters, first in crustacean muscle and later in the vertebrate CNS. As amino acids, they
have many other important biochemical roles; thus their concentration is uniformly
high throughout the nervous system. Certain areas in the spinal cord, interneurons of
the reflex arc, and a pathway from the cortex to the striatum are presumed sites of activity.
Because of the uniform glutamate and aspartate distribution, mapping of the receptors
was accomplished only recently. For the same reason, specific nonendogenous natural-
product agonists had to be used for receptor characterization, in the same manner as in
the differentiation of the nicotinic and muscarinic cholinoceptors.
NEUROTRANSMITTERS AND THEIR RECEPTORS 283