Medicinal Chemistry

4.9.1 Glutamate Receptors

The array of receptors that mediate the activities of glutamate is somewhat confusing.
Broadly speaking, the glutamate receptors can be categorized in two major groups:
ionotropic and metabotropic. (Ionotropic receptors exert their effect by influencing trans-
membrane ionic fluxes via ion channels; metabotropic receptors exert their influence by
controlling intracellular processes via G-proteins.) The ionotropic receptors may be sub-
divided into three types: N-methyl-D-aspartate (NMDA; 4.208),α-amino-3-hydroxy-4-
isoxazole propionic acid (AMPA; 4.209), and kainate (KA; 4.210). These three receptor
types are both functionally distinct and defined by distinct molecular families of recep-
tor genes. The three ionotropic receptors increase transmembrane cation conductance,
especially of Ca^2 +(in the case of the NMDA receptor). The metabotropic receptor family
is even more confusing. In 1989, the notion of metabotropic receptors was barely emerg-
ing; by 1995, there were three metabotropic receptors; by 1999 there were reportedly
eight of them. As stated above, the metabotropic receptors mediate their effects via
G-proteins. These ionotropic and metabotropic receptors influence a variety of neuro-
chemical and neurophysiological events. The ionotropic receptors, especially the NMDA
receptor, have received the greatest amount of study. They have been implicated in the
mechanism of information processing, memory, and learning, through long-term poten-
tiation of neuronal pathways. They have also been involved in pathological processes
such as epilepsy and stroke.

4.9.2 Glutamate Receptor Agonists and Antagonists

An immense literature regarding drug design and excitatory amino acids has emerged
over the past 15 years. Initial work focused strongly on the NMDA receptor. The design
of NMDA agonists and antagonists has been both helped and hindered by the complex-
ity of the NMDA receptor complex. In addition to the anticipated agonist and competi-
tive antagonist binding sites, there are a number of other functional subsites on the
receptor complex: glycine, polyamine, Zn^2 +and Mg^2 +. Each one of these additional bind-
ing sites responds functionally to either endogenous or exogenous ligands and is thus
also a reasonable target for drug design. NMDA-related drug design is an area in which
contributions from molecular modeling and physical chemistry have been invaluable.
The majority of NMDA agonists are closely related to the structure of glutamic acid.
Thus, 4-methylene-L-glutamic acid (4.211) is a potent NMDA agonist. Bioisosteric
replacement of a carboxylate group also produces agonists; D,L-(tetrazol-5-yl)glycine
(4.212), in which a tetrazole bioisostere replaces a carboxylate, is a potent NMDA

284 MEDICINAL CHEMISTRY