Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs

Metabotropic glutamate (mGlu) receptors have been considered as potential t argets for neuroprotective drugs. but the lack of specific drugs has limite d the development of neuroprotective strategies in experimental models of a cute or chronic central nervous system (CNS) disorders. The advent of poten t and centrally available subtype-selective ligands has overcome this limit ation, leading to an extensive investigation of the role of mGlu receptor s ubtypes in neurodegeneration during the last 2 years. Examples of these dru gs are the noncompetitive mGlu1 receptor antagonists, CPCCOEt and BAY-36-76 20; the noncompetitive mGlu5 receptor antagonists, 2-methyl-6-(phenylethyny l)pyridine, SIB-1893, and SIB-1757; and the potent mGlu2/3 receptor agonist s, LY354740 and LY379268. Pharmacologic blockade of mGlu I or mGlu5 recepto rs or pharmacologic activation of mGlu2/3 or mGlu4/7/8 receptors produces n europrotection in a variety of in vitro or in vivo models. MGlu1 receptor a ntagonists are promising drugs for the treatment of brain ischemia or for t he prophylaxis of neuronal damage induced by synaptic hyperactivity. MGlu5 receptor antagonists may limit neuronal damage induced by a hyperactivity o f N-methyl-d-aspartate (NMDA) receptors, because mGlu5 and NMDA receptors a re physically and functionally connected in neuronal membranes. A series of observations suggest a potential application of mGlu5 receptor antagonists in chronic neurodegenerative disorders, such as amyotrophic lateral sclero sis and Alzheimer disease. MGlu2/3 receptor agonists inhibit glutamate rele ase, but also promote the synthesis and release of neurotrophic factors in astrocytes. These drugs may therefore have a broad application as neuroprot ective agents in a variety of CNS disorders. Finally, mGlu4/7/8 receptor ag onists potently inhibit glutamate release and have a potential application in seizure disorders. The advantage of all these drugs with respect to NMDA or AMPA receptor agonists derives from the evidence that mGlu receptors do not "mediate," but rather "modulate" excitatory synaptic transmission. The refore. it can be expected that mGlu receptor ligands are devoid of the und esirable effects resulting from the inhibition of excitatory synaptic trans mission, such as sedation or an impairment of learning and memory.