Metabotropic glutamate receptors (mGluRs) consist of three major groups I-III which are involved in physiological processes such as synaptic transmission and neuronal plasticity as well as neuropathology. There are two Group I mGluRs receptor subtypes, mGluR1 and mGluR5, which are mainly localized to postsynaptic membranes. Their activation usually evokes excitation in neurons via PLC conversion of PIP2 to DAG and IP3. DAG activates PKC whereas IP3 has numerous effects including stimulation of Ca2+ release from intracellular stores.
The advent of potent and CNS penetrant subtype-selective allosteric modulators has led to an extensive investigation of the role of mGluRs in CNS diseases. E.g. pharmacological blockade of mGluR1 or 5 produces neuroprotection in a variety of in vitro and in vivo models suggesting a potential application of mGluR1/5 antagonists in chronic neurodegenerative disorders, such as Alzheimerīs disease and Parkinsonīs disease.
The advantage of such drugs with respect to competitive ionotropic glutamate receptor antagonists derives from the observation that mGluRs do not "mediate," but rather "modulate" excitatory synaptic transmission. It is predicted that mGluR ligands will have less undesirable effects resulting from the inhibition of physiological excitatory synaptic transmission.
Point mutations in the transmembrane domains of cloned mGluRs can give great insights into the binding modes of such allosteric ligands and help to develop so called computer virtual pharmacophore models of the ligand / receptor binding pocket (graphic below courtesy of Tanja Weil).
