CNS Drug Reviews, Volume 5, No. 1, Spring 1999

Glutamate receptors can be broadly classified into two subtypes: ionotropic glutamate receptors, which are ligand-gated ion channels, and metabotropic glutamate receptors (mGlu receptors), which are coupled via G proteins to second messenger systems (32). When activated, ionotropic glutamate receptors produce an influx of cations into the cell, directly depolarizing the postsynaptic neuron and thus transmitting excitatory inputs into the synapse. In contrast, mGlu receptors function to more subtly modulate glutamatergic transmission by presynaptic and postsynaptic mechanisms. mGlu receptors fall into three groups based on current pharmacology and the molecular properties of each receptor. Group I mGlu receptors include mGlu1 and mGlu5, and these receptors are coupled to phosphoinositide hydrolysis when expressed in nonneuronal cells. Group II mGlu receptors include mGlu2 and mGlu3 and, when expressed in nonneuronal cells, they are linked negatively to cAMP formation. Group III mGlu receptors are also linked negatively to cAMP formation and are the most heterogenous group, including mGlu4, mGlu6, mGlu7, and mGlu8 receptors. Each mGlu receptor subtype is uniquely and differentially distributed in the CNS. Thus, the expression of mGlu receptors in different brain regions and select synapses provides a mechanism for the CNS to modulate glutamatergic neuronal transmission within specific synapses (11,37,44). There are currently few potent and systemically active compounds that are selective agonists or antagonists for mGlu receptor subtypes. Pharmacological agents that have some selectivity for each of the three groups of mGlu receptors are known; however, such compounds generally have relatively low potency and selectivity, and have not been shown to have pharmacological effects following systemic administration. In contrast, LY354740 is a conformationally constrained analog of glutamate which is a highly potent