The metabotropic glutamate subtype 2 (mGlu ) receptor is a presynaptic membrane receptor distributed widely in brain that provides feedback inhibitory control of glutamate release. Inhibition of the mGlu receptor function with a negative allosteric modulator (NAM) enhances activity-dependent glutamate release, which may be of therapeutic benefit for the treatment of neurological and psychiatric disorders. An attractive pyrazole hit was identified after a high-throughput screening (HTS) campaign. The evolution of this hit is described by structure-activity relationship (SAR) studies on specific parts of the molecule. From near micromolar potency we could obtain compounds with single-digit nanomolar activity in the mGlu NAM GTPγS assay. In addition to SAR on in vitro potency, a more detailed overview is given with a specific set of compounds on the excellent agreement between in vitro potency, free brain concentration, and ex vivo mGlu receptor occupancy. Finally, to obtain improved drug-like compounds, plans for future research are suggested toward increasing free brain concentration while maintaining high in vitro potency.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1002/cmdc.201700101 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
GPCR oligomerization across classes: A2AR-mediated regulation of mGlu5R activation.
Int J Biol Macromol
January 2025
Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal; CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal. Electronic address:
The adenosine A receptor (AR), a class A GPCR, is a known player in neurological diseases, including Parkinson's disease and Alzheimer's disease, and is also implicated in SARS-CoV-2 infection. Recent studies have revealed its oligomerization with metabotropic glutamate receptor type 5 (mGluR), a class C G protein coupled receptor (GPCR) that exists in the homodimeric form. Simultaneous activation of both receptors synergistically enhances mGluR-mediated effects in the hippocampus.
View Article and Find Full Text PDFConformational diversity in class C GPCR positive allosteric modulation.
Nat Commun
January 2025
IGF, Université de Montpellier, CNRS, INSERM, 34094, Montpellier, France.
The metabotropic glutamate receptors (mGlus) are class C G protein-coupled receptors (GPCR) that form obligate dimers activated by the major excitatory neurotransmitter L-glutamate. The architecture of mGlu receptor comprises an extracellular Venus-Fly Trap domain (VFT) connected to the transmembrane domain (7TM) through a Cysteine-Rich Domain (CRD). The binding of L-glutamate in the VFTs and subsequent conformational change results in the signal being transmitted to the 7TM inducing G protein binding and activation.
View Article and Find Full Text PDFPreclinical and clinical study on type 3 metabotropic glutamate receptors in Parkinson's disease.
NPJ Parkinsons Dis
January 2025
Department of Molecular Pathology, IRCCS Neuromed, Pozzilli, Italy.
Metabotropic glutamate (mGlu) receptors are candidate drug targets for therapeutic intervention in Parkinson's disease (PD). Here we focused on mGlu3, a receptor subtype involved in synaptic regulation and neuroinflammation. mGlu3 mice showed an enhanced nigro-striatal damage and microglial activation in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
View Article and Find Full Text PDFPharmacology, Signaling and Therapeutic Potential of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators.
ACS Pharmacol Transl Sci
December 2024
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, VIC 3052, Australia.
Metabotropic glutamate receptors are a family of eight class C G protein-coupled receptors regulating higher order brain functions including cognition and motion. Metabotropic glutamate receptors have thus been heavily investigated as potential drug targets for treating neurological disorders. Drug discovery efforts directed toward metabotropic glutamate receptor subtype 5 (mGlu) have been particularly fruitful, with a wealth of drug candidates and pharmacological tools identified.
View Article and Find Full Text PDFDiscovery of 4-(5-Membered)Heteroarylether-6-methylpicolinamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5.
ACS Med Chem Lett
December 2024
Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
This Letter details our efforts to develop novel, non-acetylene-containing metabotropic glutamate receptor subtype 5 (mGlu) negative allosteric modulators (NAMs) with improved pharmacological properties. This endeavor involved replacing the ether-linked pyrimidine moiety, a metabolic liability, with various 5-membered heterocycles. From this exercise, we identified , a highly brain penetrant and selective mGlu NAM which displayed moderate potency against both human and rat mGlu.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!