Neuropharmacological Insight from Allosteric Modulation of mGlu Receptors

Abstract

The metabotropic glutamate (mGlu) receptors are a family of G-protein-coupled receptors (GPCRs) that regulate cell physiology throughout the nervous system. The potential of mGlu receptors as therapeutic targets has been bolstered by current research that has provided insight into the diverse modes of mGlu activation and signaling. In particular, the allosteric modulation of mGlu receptors represents a major area of focus in studies of basic pharmacology as well as drug development, largely due to the high subtype specificity achievable by targeting allosteric sites on mGlu receptors. These provide sophisticated regulation of neuronal excitability and synaptic transmission to influence behavioral output. Here, we review how these allosteric mechanisms have been leveraged preclinically to demonstrate the therapeutic potential of allosteric modulators for neurological and neuropsychiatric disorders, such as autism, cognitive impairment, Parkinson's disease (PD), stress, and schizophrenia.

Keywords: CNS; allosteric modulators; drug discovery; mGlu; neuropsychiatric disorders; stimulus bias.

Figure 1,. Key Figure. Synaptic mGlu receptor locations within the prefrontal cortex and hippocampus.

mGlu receptors mediate disparate effects at synapses of different brain regions. (A) Prefrontal cortex glutamatergic synapse. Postsynaptic mGlu3 and mGlu5 receptor activation synergizes to enhance signaling cascades. Presynaptic mGlu2 receptors act to reduce synaptic transmission. mGlu1 receptors located on interneurons mediates feed forward inhibition of pyramidal cells. (B) Hippocampal SC-CA1 synapse. mGlu3 and mGlu5 receptors interact postsynaptically to enhance signaling cascades. mGlu1 receptors activation results in SK channel inhibition, promoting excitability and NDMAR disinhibition. mGlu7 receptors located on inhibitory interneurons reduce GABA transmission. Astrocytic mGlu3 receptors lead to enhanced cAMP production and retrograde signaling onto presynaptic terminals to reduce excitatory transmission.

Figure 2.. mGlu receptor allosteric modulation induced stimulus bias.

Schematic depicting the differential effects of mGlu receptor PAMs on downstream signaling cascades. (A) Activation of mGlu receptors by the endogenous ligand (glutamate) causes activation of downstream signaling cascades. (B) Non-biased PAM causes potentiation of all downstream signaling cascades equally. (C) Biased PAM causes selective potentiation of signaling cascades.