Novel metabotropic glutamate receptor 2/3 antagonists and their therapeutic applications: a patent review (2005 – present)

Célanire, Sylvain; Sebhat, Iyassu K.; Wichmann, Juergen; Mayer, Stanislas; Schann, Stéphan; Gatti, Silvia

doi:10.1517/13543776.2014.983899

Cited by 28 publications

(31 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To further test the contribution of mGlu 2 activation to this LTD response, we synthesized and characterized the reported mGlu 2 -selective NAM MRK-8-29 (25,26). The synthesis of MRK-8-29 was completed in seven steps from commercially available 4,7-dichloroquinoline, using a modified version of the originally reported route (SI Materials and Methods).…”

Section: Resultsmentioning

confidence: 99%

Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

Walker¹,

Wenthur²,

Xiang³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Clinical studies have revealed that genetic variations in metabotropic glutamate receptor 3 (mGlu 3 ) affect performance on cognitive tasks dependent upon the prefrontal cortex (PFC) and may be linked to psychiatric conditions such as schizophrenia, bipolar disorder, and addiction. We have performed a series of studies aimed at understanding how mGlu 3 influences PFC function and cognitive behaviors. In the present study, we found that activation of mGlu 3 can induce long-term depression in the mouse medial PFC (mPFC) in vitro. Furthermore, in vivo administration of a selective mGlu 3 negative allosteric modulator impaired learning in the mPFC-dependent fear extinction task. The results of these studies implicate mGlu 3 as a major regulator of PFC function and cognition. Additionally, potentiators of mGlu 3 may be useful in alleviating prefrontal impairments associated with several CNS disorders.etabotropic glutamate receptor 3 (mGlu 3 ) has become of increasing clinical interest due to its genetic association with psychiatric conditions. For example, several studies have identified single-nucleotide polymorphisms (SNPs) in GRM3, the human gene encoding mGlu 3 , that are associated with poor performance on cognitive tests that are dependent on function of the prefrontal cortex (PFC) and hippocampus (1, 2). Additionally, these SNPs have also been associated with variations in functional magnetic resonance imaging (fMRI) indexes of prefrontal cortical activity during working memory tasks (1, 3). Moreover, converging lines of evidence indicate that GRM3 represents a major locus associated with schizophrenia (1, 2, 4), bipolar disorder (5, 6), and substance abuse disorders (6-8). Because mGlu 3 is densely expressed in PFC (9), a brain region implicated as a site of pathology in these disorders (10-12), this genetic evidence has led to an increased interest in determining the role of mGlu 3 in regulating PFC function and behavior.Previous studies have revealed that pharmacological activation of group II mGlu receptors (mGlu 2 and mGlu 3 ) results in longterm depression (LTD) of excitatory transmission in layer V of the rat medial prefrontal cortex (mPFC) (13-16). Although it is not known whether induction of LTD in the mPFC is mediated by mGlu 2 or mGlu 3 , previous studies suggest that presynaptically localized mGlu 2 is typically responsible for inhibition of synaptic transmission by group II mGlu receptor agonists at other synapses (17-23). However, evidence suggests that induction of LTD in the mPFC is dependent upon activation of a postsynaptic group II mGlu receptor (15, 16), suggesting that this response is mechanistically distinct from presynaptic effects of group II mGlu receptor agonists on transmission at other synapses. Unfortunately, a lack of pharmacological agents that can selectively antagonize mGlu 3 or mGlu 2 has impaired progress in this area. To allow us to begin studies aimed at understanding the role of mGlu 3 in regulation of mPFC function, we developed a series of negative allosteric modulator...

show abstract

Section: Resultsmentioning

confidence: 99%

Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

Walker¹,

Wenthur²,

Xiang³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The work on novel glutamatergic antidepressant drug candidates also has investigated ligands to other mGlu receptors, most notably mGlu2/3 antagonists (Sanacora et al, 2012;Krystal et al, 2013;Celanire et al, 2015). The literature and our own work suggest that mGlu2/3 inhibitors have procognitive properties in a range of preclinical models of short-term and long-term memory, executive function, and impulse control (Higgins et al, 2004;Spinelli et al, 2005;Marek, 2010;Goeldner et al, 2013), which makes them interesting candidates to address cognitive deficits in MDD (Goeldner et al, 2013).…”

Section: Discussionmentioning

confidence: 96%

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Lindemann

Porter

Scharf

et al. 2015

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and secondgeneration antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wakepromoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.

show abstract

“…236 Again, two highly functionalized glutamate analogues, LY341495 ( 49 ) 237 and MGS0039 ( 50 ) 238 (Figure 10), were employed for the vast majority of this preclinical work. Whereas MGS0039 ( 50 ) is an analogue of mGlu 2/3 agonist LY354740 ( 45 ), LY341495 ( 49 ) is quite structurally distinct.…”

Section: 2 Allosteric Modulators Of the Mglu2 And Mglu3 Receptorsmentioning

confidence: 99%

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

et al. 2016

View full text Add to dashboard Cite

Allosteric modulation of GPCRs has initiated a new era of basic and translational discovery, filled with therapeutic promise yet fraught with caveats. Allosteric ligands stabilize unique conformations of the GPCR that afford fundamentally new receptors, capable of novel pharmacology, unprecedented subtype selectivity, and unique signal bias. This review provides a comprehensive overview of the basics of GPCR allosteric pharmacology, medicinal chemistry, drug metabolism, and validated approaches to address each of the major challenges and caveats. Then, the review narrows focus to highlight recent advances in the discovery of allosteric ligands for metabotropic glutamate receptor subtypes 1–5 and 7 (mGlu 1–57) highlighting key concepts (“molecular switches”, signal bias, heterodimers) and practical solutions to enable the development of tool compounds and clinical candidates. The review closes with a section on late-breaking new advances with allosteric ligands for other GPCRs and emerging data for endogenous allosteric modulators.

show abstract

Novel metabotropic glutamate receptor 2/3 antagonists and their therapeutic applications: a patent review (2005 – present)

Abstract: Recent advances in the prodrug approach of novel mGlu2/3 orthosteric antagonists combined with the design of novel mGlu2/3 and mGlu2 negative allosteric modulators provide new therapeutic opportunities for neurologic and psychiatric disorders.

Cited by 28 publications

References 54 publications

Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

Contact Info

Product

Resources

About