Discovery of novel positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5)

Varnes, Jeffrey; Marcus, Andrew P.; Mauger, Russell C.; Throner, Scott; Hoesch, Valerie; King, Megan M.; Wang, Xia; Sygowski, Linda A.; Spear, Nathan; Gadient, Reto A.; Brown, Dean G.; Campbell, James B.

doi:10.1016/j.bmcl.2011.01.027

Cited by 29 publications

(24 citation statements)

References 10 publications

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“…82 Solubility was a key feature they wished to understand within the series while maintaining an appropriate cLogP. Replacement of the pyrimidine with various groups including azaindoline (38À39), benzimidazole (40), azabenzimidazole (41), or N-methyl 8-azaoxazine (42) was incorporated with the phenyl acetylene moiety retained throughout.…”

Section: Acetylenesmentioning

confidence: 99%

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

Stauffer

2011

ACS Chem. Neurosci.

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ABSTRACT:This Review describes recent trends in the development of small molecule mGlu 5 positive allosteric modulators (PAMs). A large body of pharmacological, genetic, electrophysiological, and in vivo behavioral evidence has accumulated over the past decade which continues to support the hypothesis and rationale for the activation of the metabotropic glutamate receptor subtype 5 (mGlu 5 ) as a viable and promising target for the development of novel antipsychotics. Until recently, functionally efficacious and potent mGlu 5 PAMs have been somewhat structurally limited in scope and slow to emerge. This Review will discuss efforts since late 2008 which have provided novel mGlu 5 PAM chemotypes, offering ligands with a diverse range of pharmacological, physicochemical, and DMPK properties that were previously unavailable. In addition, significant biological studies of importance in the past few years using the well established PAMs known as DFB, CPPHA, CDPPB, and ADX-47273 will be discussed. KEYWORDS:Metabotropic, mGlu 5 , schizophrenia, allosteric, positive allosteric modulator, DFB, CPPHA, CDPPB, ADX-47273, glutamate G lutamate is the single most important excitatory neurotransmitter in the mammalian central nervous system (CNS). 1 The concentration of glutamate within the cytoplasm of glutamatergic neurons is several times more than that of any other amino acid, approximately 5À10 mM, and within synaptic vesicles glutamate reserves can be significantly higher. The two major receptor classes that are known to be modulated by glutamate include ionotropic glutamate receptors (iGlus), which are multimeric glutamate-gated cation channels, and metabotropic glutamate receptors (mGlus), which are seven transmembrane heptahelical (7TM) spanning proteins coupled to effector G-proteins. 2 Ionotropic glutamate receptors are responsible for fast acting glutaminergic transmission in the CNS and are mediated by the three subclasses of iGlus: the R-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors. All three iGlu channels undergo a conformational change and open in response to glutamate binding and induce excitatory post synaptic current, with the NMDA receptor perhaps best characterized and central to many hypotheses of CNS pathologies. A wide range of neurological disorders including chronic pain, schizophrenia, Alzheimer's disease, epilepsy, drug addiction, and fragile X syndrome have been associated with dysfunction of glutamatergic systems. 1,3 In contrast to ionotropic glutamate receptors, metabotropic glutamate receptors bind glutamate to modulate either presynaptic neurotransmitter release or postsynaptic excitatory neurotransmission.Allosteric modulation of metabotropic glutamate receptors as a glutamate-based approach for therapeutic intervention, either via enhancing or inhibiting endogenous agonist responses, is a highly active area of research and drug development. 3À7 Allosteric mechanisms of receptor modulation provide several potential advantages o...

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Section: Acetylenesmentioning

confidence: 99%

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

Stauffer

2011

ACS Chem. Neurosci.

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“…A growing body of evidence suggests that selective activators of the mGlu 5 subtype could provide an exciting new approach for treatment of schizophrenia and other disorders that lead to impaired cognitive function (Gregory et al, 2011;Vinson and Conn, 2012). Although discovery of selective mGlu 5 agonists that have drug-like properties has been challenging, there have been major advances in development of highly selective positive allosteric modulators (PAMs) for mGlu 5 (Liu et al, 2008;Conn et al, 2009;Stauffer, 2011;Varnes et al, 2011;Packiarajan et al, 2012). A diverse range of selective mGlu 5 PAMs have now been identified that have efficacy in animal models used to predict potential antipsychotic and cognitive enhancing activity (Gregory et al, 2011;Vinson and Conn, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Selective mGlu 5 PAMs have been developed from multiple chemical scaffolds (O'Brien et al, 2004;Kinney et al, 2005;Chen et al, 2007;Liu et al, 2008;Hammond et al, 2010;Rodriguez et al, 2010;Lamb et al, 2011;Stauffer, 2011;Varnes et al, 2011;Noetzel et al, 2012;Packiarajan et al, 2012); the majority of these mGlu 5 PAMs bind to the same site as the prototypical mGlu 5 negative allosteric modulator (NAM) MPEP (2-Methyl-6-(phenylethynyl)pyridine), located in the top third of the transmembrane spanning domains, involving transmembrane domains 3, 6, and 7 (Gregory et al, 2011). However, at least two mGlu 5 PAMs, CPPHA (N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl] phenyl)-2-hydroxybenzamide) (O'Brien et al, 2004;Zhao et al, 2007;Chen et al, 2008) and VU0357121 (Hammond et al, 2010), have been identified that interact noncompetitively with the MPEP site.…”

Section: Introductionmentioning

confidence: 99%

A Novel Metabotropic Glutamate Receptor 5 Positive Allosteric Modulator Acts at a Unique Site and Confers Stimulus Bias to mGlu5 Signaling

et al. 2013

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Metabotropic glutamate receptor 5 (mGlu 5 ) is a target for the treatment of central nervous system (CNS) disorders, such as schizophrenia and Alzheimer's disease. Furthermore, mGlu 5 has been shown to play an important role in hippocampal synaptic plasticity, specifically in long-term depression (LTD) and longterm potentiation (LTP), which is thought to be involved in cognition. Multiple mGlu 5 -positive allosteric modulators (PAMs) have been developed from a variety of different scaffolds. Previous work has extensively characterized a common allosteric site on mGlu 5 , termed the MPEP (2-Methyl-6-(phenylethynyl)pyridine) binding site. However, one mGlu 5 PAM, CPPHA (N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl)-2-hydroxybenzamide), interacts with a separate allosteric site on mGlu 5. Using cell-based assays and brain slice preparations, we characterized the interaction of a potent and efficacious mGlu 5 PAM from the CPPHA series termed NCFP (N-(4-chloro-2-((4-fluoro-1,3-dioxoisoindolin-2-yl)methyl)phenyl)picolinamide). NCFP binds to the CPPHA site on mGlu 5 and potentiates mGlu 5 -mediated responses in both recombinant and native systems. However, NCFP provides greater mGlu 5 subtype selectivity than does CPPHA, making it more suitable for studies of effects on mGlu 5 in CNS preparations. Of interest, NCFP does not potentiate responses involved in hippocampal synaptic plasticity (LTD/ LTP), setting it apart from other previously characterized MPEP site PAMs. This suggests that although mGlu 5 PAMs may have similar responses in some systems, they can induce differential effects on mGlu 5 -mediated physiologic responses in the CNS. Such stimulus bias by mGlu 5 PAMs may complicate drug discovery efforts but would also allow for specifically tailored therapies, if pharmacological biases can be attributed to different therapeutic outcomes.

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“…A broad range of mGlu 5 PAMs that induce robust increases in responses of mGlu 5 to glutamate have been identified (O'Brien et al, 2004;Kinney et al, 2005;Chen et al, 2007;Liu et al, 2008;Rodriguez et al, 2010;Varnes et al, 2011). Of interest, mGlu 5 PAMs can differ in ways that could have an important impact on their overall physiological and behavioral effects.…”

Section: Introductionmentioning

confidence: 99%

Functional Impact of Allosteric Agonist Activity of Selective Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 in Regulating Central Nervous System Function

Noetzel

Rook²,

Vinson³

et al. 2011

Mol Pharmacol

113

147

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Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu 5 ) have emerged as an exciting new approach for the treatment of schizophrenia and other central nervous system (CNS) disorders. Of interest, some mGlu 5 PAMs act as pure PAMs, only potentiating mGlu 5 responses to glutamate whereas others [allosteric agonists coupled with PAM activity (ago-PAMs)] potentiate responses to glutamate and have intrinsic allosteric agonist activity in mGlu 5 -expressing cell lines. All mGlu 5 PAMs previously shown to have efficacy in animal models act as ago-PAMs in cell lines, raising the possibility that allosteric agonist activity is critical for in vivo efficacy. We have now optimized novel mGlu 5 pure PAMs that are devoid of detectable agonist activity and structurally related mGlu 5 ago-PAMs that activate mGlu 5 alone in cell lines. Studies of mGlu 5 PAMs in cell lines revealed that ago-PAM activity is dependent on levels of mGlu 5 receptor expression in human embryonic kidney 293 cells, whereas PAM potency is relatively unaffected by levels of receptor expression. Furthermore, ago-PAMs have no agonist activity in the native systems tested, including cortical astrocytes and subthalamic nucleus neurons and in measures of long-term depression at the hippocampal Schaffer collateral-CA1 synapse. Finally, studies with pure PAMs and ago-PAMs chemically optimized to provide comparable CNS exposure revealed that both classes of mGlu 5 PAMs have similar efficacy in a rodent model predictive of antipsychotic activity. These data suggest that the level of receptor expression influences the ability of mGlu 5 PAMs to act as allosteric agonists in vitro and that ago-PAM activity observed in cell-based assays may not be important for in vivo efficacy.

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Discovery of novel positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5)

Cited by 29 publications

References 10 publications

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

A Novel Metabotropic Glutamate Receptor 5 Positive Allosteric Modulator Acts at a Unique Site and Confers Stimulus Bias to mGlu5 Signaling

Functional Impact of Allosteric Agonist Activity of Selective Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 in Regulating Central Nervous System Function

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Discovery of novel positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5)

Cited by 29 publications

References 10 publications

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu5)

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu5)

A Novel Metabotropic Glutamate Receptor 5 Positive Allosteric Modulator Acts at a Unique Site and Confers Stimulus Bias to mGlu5 Signaling

Functional Impact of Allosteric Agonist Activity of Selective Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 in Regulating Central Nervous System Function

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Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)