Discovery of Novel Central Nervous System Penetrant Metabotropic Glutamate Receptor Subtype 2 (mGlu2) Negative Allosteric Modulators (NAMs) Based on Functionalized Pyrazolo[1,5-a]pyrimidine-5-carboxamide and Thieno[3,2-b]pyridine-5-carboxamide Cores

2018 ◽  
Vol 62 (1) ◽  
pp. 378-384 ◽  
Author(s):  
Elizabeth S. Childress ◽  
Joshua M. Wieting ◽  
Andrew S. Felts ◽  
Megan M. Breiner ◽  
Madeline F. Long ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Subtype ◽  
Allosteric Modulators ◽  
Metabotropic Glutamate

scholarly journals Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

2018 ◽  
Vol 28 (10) ◽  
pp. 1679-1685 ◽  
Author(s):  
Andrew S. Felts ◽  
Alice L. Rodriguez ◽  
Ryan D. Morrison ◽  
Anna L. Blobaum ◽  
Frank W. Byers ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Subtype ◽  
Allosteric Modulators ◽  
Metabotropic Glutamate

scholarly journals Design of 4-Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as Selective Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 2

2015 ◽  
Vol 58 (22) ◽  
pp. 9027-9040 ◽  
Author(s):  
Andrew S. Felts ◽  
Alice L. Rodriguez ◽  
Katrina A. Smith ◽  
Julie L. Engers ◽  
Ryan D. Morrison ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Subtype ◽  
Allosteric Modulators ◽  
Metabotropic Glutamate

scholarly journals Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

2019 ◽  
Vol 29 (1) ◽  
pp. 47-50 ◽  
Author(s):  
Andrew S. Felts ◽  
Katrina A. Bollinger ◽  
Christopher J. Brassard ◽  
Alice L. Rodriguez ◽  
Ryan D. Morrison ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Subtype ◽  
Allosteric Modulators ◽  
Metabotropic Glutamate

Biased agonism and allosteric modulation of metabotropic glutamate receptor 5

2018 ◽  
Vol 132 (21) ◽  
pp. 2323-2338 ◽  
Author(s):  
Phuc N.H. Trinh ◽  
Lauren T. May ◽  
Katie Leach ◽  
Karen J. Gregory
Keyword(s):  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Allosteric Modulation ◽  
Receptor Subtype ◽  
Allosteric Modulators ◽  
Biased Agonism ◽  
Metabotropic Glutamate ◽  
Promising Target ◽  
The Central Nervous System

Metabotropic glutamate receptors belong to class C G-protein-coupled receptors and consist of eight subtypes that are ubiquitously expressed throughout the central nervous system. In recent years, the metabotropic glutamate receptor subtype 5 (mGlu5) has emerged as a promising target for a broad range of psychiatric and neurological disorders. Drug discovery programs targetting mGlu5 are primarily focused on development of allosteric modulators that interact with sites distinct from the endogenous agonist glutamate. Significant efforts have seen mGlu5 allosteric modulators progress into clinical trials; however, recent failures due to lack of efficacy or adverse effects indicate a need for a better understanding of the functional consequences of mGlu5 allosteric modulation. Biased agonism is an interrelated phenomenon to allosterism, describing how different ligands acting through the same receptor can differentially influence signaling to distinct transducers and pathways. Emerging evidence demonstrates that allosteric modulators can induce biased pharmacology at the level of intrinsic agonism as well as through differential modulation of orthosteric agonist-signaling pathways. Here, we present key considerations in the discovery and development of mGlu5 allosteric modulators and the opportunities and pitfalls offered by biased agonism and modulation.

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