Discovery of Highly Potent, Selective, Orally Bioavailable, Metabotropic Glutamate Subtype 5 (mGlu5) Receptor Antagonists Devoid of Cytochrome P450 1A2 Inhibitory Activity.

ChemInform ◽  
2005 ◽  
Vol 36 (14) ◽  
Author(s):  
Nicholas D. Smith ◽  
et al. et al.
Keyword(s):  
Cytochrome P450 ◽  
Inhibitory Activity ◽  
Receptor Antagonists ◽  
Cytochrome P450 1A2 ◽  
Metabotropic Glutamate ◽  
Mglu5 Receptor ◽  
Orally Bioavailable

Dipyridyl amides: potent metabotropic glutamate subtype 5 (mGlu5) receptor antagonists

2005 ◽  
Vol 15 (4) ◽  
pp. 1197-1200 ◽  
Author(s):  
Céline Bonnefous ◽  
Jean-Michel Vernier ◽  
John H. Hutchinson ◽  
Janice Chung ◽  
Grace Reyes-Manalo ◽  
...  
Keyword(s):  
Receptor Antagonists ◽  
Metabotropic Glutamate ◽  
Mglu5 Receptor

scholarly journals Targeting of Metabotropic Glutamate Receptors for the Development of Novel Antidepressants

2019 ◽  
Vol 3 ◽  
pp. 247054701983771 ◽  
Author(s):  
Shigeyuki Chaki ◽  
Hiroyuki Koike ◽  
Kenichi Fukumoto
Keyword(s):  
Drug Targets ◽  
Metabotropic Glutamate Receptors ◽  
Receptor Subtype ◽  
Allosteric Modulator ◽  
Glutamatergic System ◽  
Receptor Antagonists ◽  
Metabotropic Glutamate ◽  
Mglu5 Receptor ◽  
Antidepressant Effects ◽  
Negative Allosteric Modulator

Since discovering that ketamine has robust antidepressant effects, the glutamatergic system has been proposed as an attractive target for the development of novel antidepressants. Among the glutamatergic system, metabotropic glutamate (mGlu) receptors are of interest because mGlu receptors play modulatory roles in glutamatergic transmission, consequently, agents acting on mGlu receptors might not exert the adverse effects associated with ketamine. mGlu receptors have eight subtypes that are classified into three groups, and the roles of each mGlu receptor subtype in depression are being investigated. To date, the potential use of mGlu5 receptor antagonists and mGlu2/3 receptor antagonists as antidepressants has been actively investigated, and the mechanisms underlying these antidepressant effects are being delineated. Although the outcomes of clinical trials using an mGlu5 receptor negative allosteric modulator and an mGlu2/3 receptor negative allosteric modulator have not been encouraging, these trials have been inconclusive, and additional trials using other compounds with more appropriate profiles are needed. In contrast, the roles of group III mGlu receptors have not yet been fully elucidated because of a lack of suitable pharmacological tools. Nonetheless, investigations of the use of mGlu4 and mGlu7 receptors as drug targets for the development of antidepressants have been ongoing, and some interesting evidence has been obtained.

Cyclohexenyl- and dehydropiperidinyl-alkynyl pyridines as potent metabotropic glutamate subtype 5 (mGlu5) receptor antagonists

2005 ◽  
Vol 15 (20) ◽  
pp. 4589-4593 ◽  
Author(s):  
Peter C. Chua ◽  
Johnny Y. Nagasawa ◽  
Leo S. Bleicher ◽  
Benito Munoz ◽  
Edwin J. Schweiger ◽  
...  
Keyword(s):  
Receptor Antagonists ◽  
Metabotropic Glutamate ◽  
Mglu5 Receptor

scholarly journals Metabotropic Glutamate Receptor Subtypes as Targets for Neuroprotective Drugs

2001 ◽  
Vol 21 (9) ◽  
pp. 1013-1033 ◽  
Author(s):  
Valeria Bruno ◽  
Giuseppe Battaglia ◽  
Agata Copani ◽  
Mara D'Onofrio ◽  
P. Di Iorio ◽  
...  
Keyword(s):  
Potential Application ◽  
Neuronal Damage ◽  
Glutamate Release ◽  
Receptor Subtypes ◽  
Receptor Antagonists ◽  
Cns Disorders ◽  
Receptor Agonists ◽  
Metabotropic Glutamate ◽  
Neuroprotective Drugs ◽  
Mglu5 Receptor

Metabotropic glutamate (mGlu) receptors have been considered as potential targets for neuroprotective drugs, but the lack of specific drugs has limited the development of neuroprotective strategies in experimental models of acute or chronic central nervous system (CNS) disorders. The advent of potent and centrally available subtype-selective ligands has overcome this limitation, leading to an extensive investigation of the role of mGlu receptor subtypes in neurodegeneration during the last 2 years. Examples of these drugs are the noncompetitive mGlu1 receptor antagonists, CPCCOEt and BAY-36-7620; the noncompetitive mGlu5 receptor antagonists, 2-methyl-6-(phenylethynyl)pyridine, SIB-1893, and SIB-1757; and the potent mGlu2/3 receptor agonists, LY354740 and LY379268. Pharmacologic blockade of mGlu1 or mGlu5 receptors or pharmacologic activation of mGlu2/3 or mGlu4/7/8 receptors produces neuroprotection in a variety of in vitro or in vivo models. MGlu1 receptor antagonists are promising drugs for the treatment of brain ischemia or for the prophylaxis of neuronal damage induced by synaptic hyperactivity. MGlu5 receptor antagonists may limit neuronal damage induced by a hyperactivity of N-methyl-d-aspartate (NMDA) receptors, because mGlu5 and NMDA receptors are physically and functionally connected in neuronal membranes. A series of observations suggest a potential application of mGlu5 receptor antagonists in chronic neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer disease. MGlu2/3 receptor agonists inhibit glutamate release, but also promote the synthesis and release of neurotrophic factors in astrocytes. These drugs may therefore have a broad application as neuroprotective agents in a variety of CNS disorders. Finally, mGlu4/7/8 receptor agonists potently inhibit glutamate release and have a potential application in seizure disorders. The advantage of all these drugs with respect to NMDA or AMPA receptor agonists derives from the evidence that mGlu receptors do not “mediate,” but rather “modulate” excitatory synaptic transmission. Therefore, it can be expected that mGlu receptor ligands are devoid of the undesirable effects resulting from the inhibition of excitatory synaptic transmission, such as sedation or an impairment of learning and memory.

3-[3-Fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)phenyl] -4-methylpyridine: A Highly Potent and Orally Bioavailable Metabotropic Glutamate Subtype 5 (mGlu5) Receptor Antagonist.

ChemInform ◽  
2005 ◽  
Vol 36 (14) ◽  
Author(s):  
Steve F. Poon ◽  
Brian W. Eastman ◽  
Deborah F. Chapman ◽  
Janice Chung ◽  
Merryl Cramer ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Metabotropic Glutamate ◽  
Mglu5 Receptor ◽  
Orally Bioavailable
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