Synthesis of glutamate analogues as new mGluR ligands

Glutamate ((S)-Glu) is the major excitatory amino acid in the central nervous system. It acts by stimulating ionotropic and metabotropic glutamate receptors (iGluR and mGluR respectively). Glutamate has been shown to be involved not only in many neuropathologies such as anxiety, pain, ischemia, Parkinson’s disease, epilepsy and schizophrenia. More recently, mGlu receptors have also been detected in non-neuronal cells suggesting that they could be implicated in carcinogenesis.

mGlu receptors are G-protein-coupled receptors and eight subtypes (mGluR1 to mGluR8) have been identified and classified into three groups (I-III) based upon sequence homology, transduction mechanism and pharmacological profile.

Because of their modulating properties, mGlu receptors are recognized as promising therapeutic targets and many ligands (agonists and antagonists) have been prepared to better understand the pharmacology of mGlu receptors in order to selectively activate the different groups and subtypes of receptors.

An alpha-amino acid moiety can be found in all mGlu receptors competitive ligands and most of the side chains hold an acidic function. Examination of the glutamate binding site in the mGlu receptors and pharmacological data of some ligands shows that sterically constrained structures with an optimal distance between functional groups could lead to potent and selective new ligands.

In this respect, we synthesize new analogues of glutamate by modification of the side chain and we study their pharmacological and biological activity.

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