Discovery and SAR of a novel series of non-MPEP site mGlu5 PAMs based on an aryl glycine sulfonamide scaffold

Rodriguez, Alice L.; Williams, Richard V.; Weaver, C. David; Vinson, Paige N.; Dawson, Eric S.; Steckler, Thomas; Lavreysen, Hilde; Mackie, Claire; Bartolomé, José M.; Macdonald, Gregor; Daniels, J. Scott; Niswender, Colleen M.; Jones, Carrie K.; Conn, P. Jeffrey; Lindsley, Craig W.; Stauffer, Shaun R.

doi:10.1016/j.bmcl.2012.10.068

Cited by 15 publications

(12 citation statements)

References 24 publications

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“…The hyperactivity is believed to be mediated by mesolimbic dopamine pathway and is sensitive to typical and atypical antipsychotic drugs [105]. A wide range of mGlu 5 PAMs with distinct chemical scaffolds, CDPPB 4, ADX47273 13, 5PAM523 15, VU0360172 37, VU0364289 66, and DPFE 68, caused robust reductions in amphetamine-induced hyperactivity in rodents [4,50,66,89,94,96,106], consistent with a potential role for mGlu 5 PAMs in treatment of positive symptoms of schizophrenia. Evaluation of mGlu 5 PAMs in other pharmacological models of psychosis involving indirect (amphetamine) or direct (apomorphine) dopamine agonists revealed similar results.…”

Section: Mglu Pams As a Novel Treatment For Schizophrenia: In Vivo Vasupporting

confidence: 59%

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Activation of the mGlu5 Receptor for the Treatment of Schizophrenia and Cognitive-Deficit-Associated Disorders

Williams

Jacobson

Kalinichev

et al. 2014

Small Molecule Therapeutics for Schizophrenia

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mGlu 5 receptors have been implicated in the pathophysiology of schizophrenia and cognitive dysfunction, and activation of these receptors has been proposed as a potential therapeutic strategy for treating these diseases. This chapter describes the recent progress in the discovery and development of mGlu 5 positive allosteric modulators (PAMs) as a novel therapeutic approach which does not involve a direct interaction with dopamine receptors. This new class of molecules is structurally very diverse and includes several drug-like chemical series. The pharmacological activity shown by these molecules in preclinical studies confirms their therapeutic potential in all domains of schizophrenia, including positive and negative symptoms and cognitive abnormalities. These data support the development of mGlu 5 PAMs as novel antipsychotic drugs that resonate with the glutamatergic hypofunction hypothesis of schizophrenia. The fine tuning of the functional activity and the clarification of biased signaling pathways in different chemical series may provide clues to achieve efficacy and a good safety profile for novel pharmacotherapies.

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Section: Mglu Pams As a Novel Treatment For Schizophrenia: In Vivo Vasupporting

confidence: 59%

“…VU0357121 60 shares a functional interaction with the MPEP site [79]. In contrast, CPPHA 2 and VU400100 75 did not displace [ 3 H]-methoxyPEPy binding [96]. VU400100 75 is structurally unrelated to CPPHA 2, and there is no published data regarding its interaction with that site, so its binding site is currently unknown.…”

Section: Radiolabelled Agentsmentioning

confidence: 82%

Activation of the mGlu5 Receptor for the Treatment of Schizophrenia and Cognitive-Deficit-Associated Disorders

Williams

Jacobson

Kalinichev

et al. 2014

Small Molecule Therapeutics for Schizophrenia

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“…While the majority of PAMs bind at the MPEP ( 40 ) site, CPPHA ( 6 ) [238, 239], VU0034403 ( 43 ) [240] and VU0357121 ( 44 ) [241], have been shown to potentiate mGlu 5 at a site distinct from the MPEP allosteric site. It is not yet clear if the unique conformations stabilized by ligands at the other allosteric sites offer advantages or disadvantages over modulation via the MPEP ( 40 ) site, but it is known that CPPHA ( 6 ) displays ligand-biased signaling [242].…”

Section: Allosteric Approaches Targeting Glutamatergic Synaptic Transmentioning

confidence: 99%

Allosteric Modulators for the Treatment of Schizophrenia: Targeting Glutamatergic Networks

Menniti

Lindsley²,

Conn³

et al. 2013

CTMC

Self Cite

138

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Schizophrenia is a highly debilitating mental disorder which afflicts approximately 1% of the global population. Cognitive and negative deficits account for the lifelong disability associated with schizophrenia, whose symptoms are not effectively addressed by current treatments. New medicines are needed to treat these aspects of the disease. Neurodevelopmental, neuropathological, genetic, and behavioral pharmacological data indicate that schizophrenia stems from a dysfunction of glutamate synaptic transmission, particularly in frontal cortical networks. A number of novel pre- and postsynaptic mechanisms affecting glutamatergic synaptic transmission have emerged as viable targets for schizophrenia. While developing orthosteric glutamatergic agents for these targets has proven extremely difficult, targeting allosteric sites of these targets has emerged as a promising alternative. From a medicinal chemistry perspective, allosteric sites provide an opportunity of finding agents with better drug-like properties and greater target specificity. Furthermore, allosteric modulators are better suited to maintaining the highly precise temporal and spatial aspects of glutamatergic synaptic transmission. Herein, we review neuropathological and genomic/genetic evidence underscoring the importance of glutamate synaptic dysfunction in the etiology of schizophrenia and make a case for allosteric targets for therapeutic intervention. We review progress in identifying allosteric modulators of AMPA receptors, NMDA receptors, and metabotropic glutamate receptors, all with the aim of restoring physiological glutamatergic synaptic transmission. Challenges remain given the complexity of schizophrenia and the difficulty in studying cognition in animals and humans. Nonetheless, important compounds have emerged from these efforts and promising preclinical and variable clinical validation has been achieved.

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“…This suggests that the intact full-length receptor is required for this alternate allosteric site and/or receptor dimerization is also necessary. Also for mGlu 5 , VU0357121 [4-butoxy-N-(2,4-difluorophenyl) (Hammond et al, 2010;Gregory et al, 2012;Rodriguez et al, 2012). Multiple mGlu 1 PAM scaffolds have also been flagged as binding to alternate allosteric site(s) based on no or incomplete displacement of the allosteric radioligand [ 3 H]R214127 .…”

Section: Additional Mglu Allosteric Sitesmentioning

confidence: 99%

Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation

Gregory

Conn

2015

Mol Pharmacol

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The metabotropic glutamate (mGlu) receptors are a group of eight family C G protein-coupled receptors that are expressed throughout the central nervous system (CNS) and periphery. Within the CNS the different subtypes are found in neurons, both pre-and/or postsynaptically, where they mediate modulatory roles and in glial cells. The mGlu receptor family provides attractive targets for numerous psychiatric and neurologic disorders, with the majority of discovery programs focused on targeting allosteric sites, with allosteric ligands now available for all mGlu receptor subtypes. However, the development of allosteric ligands remains challenging. Biased modulation, probe dependence, and molecular switches all contribute to the complex molecular pharmacology exhibited by mGlu receptor allosteric ligands. In recent years we have made significant progress in our understanding of this molecular complexity coupled with an increased understanding of the structural basis of mGlu allosteric modulation.

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Discovery and SAR of a novel series of non-MPEP site mGlu5 PAMs based on an aryl glycine sulfonamide scaffold

Abstract: Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu5 PAM chemotype.

Cited by 15 publications

References 24 publications

Activation of the mGlu5 Receptor for the Treatment of Schizophrenia and Cognitive-Deficit-Associated Disorders

Activation of the mGlu5 Receptor for the Treatment of Schizophrenia and Cognitive-Deficit-Associated Disorders

Allosteric Modulators for the Treatment of Schizophrenia: Targeting Glutamatergic Networks

Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation

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