Structural basis of positive allosteric modulation of metabotropic glutamate receptor activation and internalization.

The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane domains (TMDs) to drive intracellular signaling. Pharmacologically, mGluRs can be targeted at the LBDs by glutamate and synthetic orthosteric compounds or at the TMDs by allosteric modulators. Despite the potential of allosteric compounds as therapeutics, an understanding of the functional and structural basis of their effects is limited.

Structural basis of allosteric modulation of metabotropic glutamate receptor activation and desensitization.

Unlabelled: The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane domains (TMDs) to drive intracellular signaling. Pharmacologically, mGluRs can be targeted either at the LBDs by glutamate and synthetic orthosteric compounds or at the TMDs by allosteric modulators. Despite the potential of allosteric TMD-targeting compounds as therapeutics, an understanding of the functional and structural basis of their effects on mGluRs is limited.

Positive allosteric modulators (PAMs) of the group II metabotropic glutamate receptors: Design, synthesis, and evaluation as ex-vivo tool compounds.

This letter describes synthesis and evaluation of two series of dual mGlu/mGlu positive allosteric modulators with moderate mGlu potency and robust mGlu potency in thallium flux assays. These compounds were profiled their ability to modulate mGlu-mediated signaling in central neurons by co-application of a selective mGlu NAM to isolate mGlu-selective effects. Using acute mouse brain slices from the prefrontal cortex, potentiation of group II mGlu receptor agonist Ca signaling in PFC pyramidal cells with either the dual mGlu/mGlu PAM 16e or 23d demonstrated effects mediated selectively via mGlu.

DARK Classics in Chemical Neuroscience: Kratom.

The psychoactive plant kratom is a native plant to Southeast Asia, and its major bioactive alkaloid is mitragynine. Mitragynine exerts its analgesic properties by acting on the opioid receptors. One of its active metabolites, 7-hydroxymytraginine, is found to be 40 times more potent than mitragynine and 10 times more potent than morphine.

Further exploration of an N-aryl phenoxyethoxy pyridinone-based series of mGlu NAMs: Challenging SAR, enantiospecific activity and in vivo efficacy.

This letter describes the further optimization of a series of mGlu NAMs based on an N-aryl phenoxyethoxy pyridinone core. A multidimensional optimization campaign, with focused matrix libraries, quickly established challenging SAR, enantiospecific activity, differences in assay read-outs (Ca flux via a promiscuous G protein (G) versus native coupling to GIRK channels), identified both full and partial mGlu NAMs and a new in vivo tool compound, VU6017587. This mGlu NAM showed efficacy in tail suspension, elevated zero maze and marble burying, suggesting selective inhibition of mGlu affords anxiolytic-like and antidepressant-like phenotypes in mice.