SELECTIVE METABOTROPIC RECEPTOR AGONISTS DISTINGUISH NON-IONOTROPIC GLUTAMATE BINDING-SITES

Metabotropic glutamate receptors (mGluRs) are thought to mediate diver se processes in brain including synaptic plasticity and excitotoxicity . These receptors are often divided into three groups by their pharmac ological profiles. [H-3]Glutamate binding in the presence of compounds selective for ionotropic glutamate receptors can be used as a general assay for these receptors; subtypes of this non-ionotropic [H-3]gluta mate binding differ in both pharmacology and anatomical distribution, and are differentially sensitive to quisqualate. The characteristics o f these binding sites are consistent with those of group 1 (high-affin ity quisqualate) and group 2 (low-affinity quisqualate) mGluRs. Under our assay conditions, no [H-3]glutamate binding to group 3-like (L-AP4 sensitive) sites could be demonstrated. We have attempted to characte rize particular agents which may selectively measure [H-3]glutamate bi nding to mGluR subtypes, We used two isomers of 2-(carboxycyclopropyl) glycine, L-CCG-I and L-CCG-II, and the (2S,1'R,2'R,3'R) isomer of 2-(2 ,3-dicarboxycyclopropyl)glycine (DCG-IV) as competitors of non-ionotro pic [H-3]glutamate binding sites. DCG-IV clearly distinguishes two bin ding sites. Quantitative levels of DCG-IV binding by anatomic region c orrelate with quisqualate-defined binding subtypes: high-affinity DCG- IV binding correlates with low-affinity quisqualate binding, whereas l ow-affinity DCG-IV binding correlates with high-affinity quisqualate b inding. L-CCG-II displaces only one type of non-ionotropic [3H]glutama te binding, corresponding to high-affinity quisqualate binding. Theref ore DCG-IV and L-CCG-II at appropriate concentrations appear to distin guish binding to putative group 2 vs. group 1 mGluRs, L-CCG-I displace s both high-and low-affinity quisqualate binding sites, but unlike the other two compounds, does not clearly distinguish between them. (C) 1 997 Elsevier Science B.V.