A series of potent non-acetylinic negative allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5 NAMs) was developed starting from HTS screening hit 1. Potency was improved via iterative SAR, and physicochemical properties were optimized to deliver orally bioavailable compounds acceptable for in vivo testing. A lead molecule from the series demonstrated dose-dependent activity in the second phase of the rat formalin test from 30 mg/kg, and a preliminary PK/PD relationship was established.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmcl.2013.06.044 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Blockade of mGluR1 and mGluR5 in the lateral habenula produces the opposite effects in the regulation of depressive-like behaviors in the hemiparkinsonian rats.
Exp Neurol
January 2025
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. Electronic address:
Depression is one of the most common non-motor symptoms in Parkinson's disease (PD) and the hyperactivity of the lateral habenula (LHb) may contribute to depression. The present study was performed to investigate the effects and mechanisms of group I metabotropic glutamate receptors (mGluRs) in the LHb on PD-related depressive-like behaviors. Unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) were used to establish the PD rat model.
View Article and Find Full Text PDFGPCR 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 PDFThe anti-dyskinetic effect of the clinic-ready mGluRpositive allosteric modulator AZD8529 in the 6-OHDA-lesioned rat.
Naunyn Schmiedebergs Arch Pharmacol
January 2025
Neurodegenerative Disorders Research Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, QC, H3A 2B4, Canada.
L-3,4-dihydroxyphenylalanine (L-DOPA) remains the main treatment for motor symptoms of Parkinson's disease (PD). However, chronic use is associated with the development of complications such as L-DOPA-induced dyskinesia. We previously demonstrated that LY-487,379, a highly selective metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulator (PAM), reduces the severity of L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD, without interfering with the anti-parkinsonian action of L-DOPA.
View Article and Find Full Text PDFRealistic mossy fiber input patterns to unipolar brush cells evoke a continuum of temporal responses comprised of components mediated by different glutamate receptors.
Elife
January 2025
Department of Neurobiology, Harvard Medical School, Boston, United States.
Unipolar brush cells (UBCs) are excitatory interneurons in the cerebellar cortex that receive mossy fiber (MF) inputs and excite granule cells. The UBC population responds to brief burst activation of MFs with a continuum of temporal transformations, but it is not known how UBCs transform the diverse range of MF input patterns that occur in vivo. Here, we use cell-attached recordings from UBCs in acute cerebellar slices to examine responses to MF firing patterns that are based on in vivo recordings.
View Article and Find Full Text PDFNon-canonical Roles of Complement in the CNS: From Synaptic Organizer to Presynaptic Modulator of Glutamate Transmission.
Curr Neuropharmacol
January 2025
Department of Pharmacy, DIFAR, Pharmacology and Toxicology Section, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy.
The central nervous system (CNS) is not an immune-privileged compartment, but it is intimately intertwined with the immune system. Among the components shared by the two compartments is the complement, a main constituent of innate immunity, which is also produced centrally and controls the development and organization of synaptic connections. Complement is considered a doubled-faced system that, besides controlling the physiological development of the central network, also subserves synaptic engulfment pivotal to the progression of neurodegenerative diseases.
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!