“...considerable effort has been directed at developing selective pharmacological ligands to probe glutamate receptor function and as putative novel therapeutic agents.”

This paper reviews the emerging class of metabotropic glutamate receptor allosteric modulators. Glutamate is the major excitatory neurotransmitter in the brain and, thus, glutamate signal transduction pathways are of fundamental importance in normal brain physiology and also in pathophysiological states. Accordingly, considerable effort has been directed at developing selective pharmacological ligands to probe glutamate receptor function and as putative novel therapeutic agents. Glutamate activates both ionotropic receptors (glutamate-gated ion channels) and a family of G-protein-coupled receptors (metabotropic glutamate receptors [mGluRs]). A number of selective mGluR competitive agonist and antagonist ligands have been identified, many of which are substituted or constrained amino acids. These compounds represent valuable pharmacological tools.

However, identification of such orthosteric site ligands selective for individual mGluRs has proved difficult and the chemical tractability and pharmacokinetic profiles of many of the amino acid templates is poor. Recently, a number of non-competitive, allosteric mGluR ligands have been identified, including antagonists, inverse agonists, and positive allosteric modulators, some of which are highly selective for individual members of the receptor family. In addition to improved selectivity, these ligands offer the potential for increased chemical tractability. Positive allosteric modulation, in particular, may offer advantages compared with orthosteric receptor agonism. Whilst systemic delivery of orthosteric agonists results in receptor activation without spatial or temporal control, administration of positive modulators should result in the potentiation of physiological glutamate-mediated receptor activation with a reduced liability for receptor desensitization and/or tolerance.

Accordingly, the emerging field of positive and negative allosteric modulation of mGluRs offers exciting potential both for further investigation of the physiological and pathophysiological roles of this receptor family and for the development of novel therapeutics for neurological and psychiatric disorders.

The paper highlights the emerging therapeutic potential of metabotropic glutamate receptor allosteric modulators which are the focus of investigation in a number of academic and industrial laboratories.

Neurons in the brain communicate with each other via release of signalling molecules (neurotransmitters) at specialized connections known as synapses. Glutamate is a major neurotransmitter in the central nervous system. It is released in response to neuronal activity at synapses where it interacts with specialized proteins known as receptors to elicit a response in the neighboring neuron. Modulation of glutamate receptor signalling has been proposed as a therapeutic target for a variety of nervous system disorders including Alzheimer’s disease, anxiety, pain, and schizophrenia. Allosteric modulators of the metabotropic glutamate receptor family are a novel class of molecule that can modulate the glutamate-mediated signal and which offer the potential to develop novel therapeutic agents for these and other disorders.

The metabotropic glutamate receptor family members have attracted attention as putative therapeutic targets since their discovery. Following the description of a number of mGluR negative allosteric modulators, I was part of the research team at F. Hoffmann-La Roche Ltd. in Basel, Switzerland, that reported the first mGluR positive allosteric modulators (Knoflach et al., Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action and binding site, Proc. Natl. Acad. Sci. 98: 13402-13407, 2001).