L-Glutamate, a major neurotransmitter in excitatory synaptic pathways of the mammalian central nervous system (CNS)(1), plays an important role in many integrative brain functions (1-4). Glutamate receptors have been classified into two distinctive groups termed ionotropic and metabotropic receptors (1-4). The ionotropic receptors (iGluRs) consist of N-methyl-D-aspartate (NMDA), โฃ-amino-3-hydroxy-5-methyl-4isoxazolepropionate (AMPA), and kainate receptors that contain glutamate-gated, cation-specific ion channels. The metabotropic glutamate receptors (mGluRs), however, are different both functionally and pharmacologically from ionotropic receptors. They are coupled to G-proteins that mediate a variety of transduction mechanisms(5).
In recent years we have witnessed a growing interest in the field of mGluRs, due to the intriguing therapeutic opportunities offered by the modulation of its members(6). To date eight cloned mGluRs have been characterized and classified into three subgroups according to their sequence homology, signal transduction mechanism, and agonist selectivity (7-9). The group I mGluRs include mGluR1 and mGluR5, which are potently activated by quisqualate resulting in an increase in phosphoinositide hydrolysis. In contrast, group II including mGluR2 and mGluR3 and group III that contains mGluR4, mGluR6, mGluR7, and mGluR8 are negatively linked to adenylyl cyclase. However, they can be distinguished by their marked agonist selectivity. The former effectively interacts with (2S,1ะS,2ะS)-2-(carboxycyclopropyl)glycine (L-CCG-I), whereas the latter potently interacts with (S)-2-amino-4-phosphonobutyric acid (L-AP4). Preliminary studies have revealed that the different subtypes may contribute differently to the regulation of synaptic transmission, as well as in the etiology of neurological disorders (7-10). These disorders include epilepsy, focal and global ischemia, pain, and neurodegenerative diseases. In order to better characterize the roles of mGluRs in physiological processes, there is an important need to develop novel, high affinity ligands which are family and subtype specific. Many advances have been made in the identification of useful ligands with subtype selectivity in the