Optimization of an ether series of mGlu5 positive allosteric modulators: Molecular determinants of MPEP-site interaction crossover

Manka, Jason; Vinson, Paige N.; Gregory, Karen J.; Williams, Richard V.; Gogi, Kiran; Days, Emily; Jadhav, Satya; Herman, Elizabeth J.; Lavreysen, Hilde; Mackie, Claire; Bartolomé, José M.; Macdonald, Gregor; Steckler, Thomas; Daniels, J. Scott; Weaver, C. David; Niswender, Colleen M.; Jones, Carrie K.; Conn, P. Jeffrey; Lindsley, Craig W.; Stauffer, Shaun R.

doi:10.1016/j.bmcl.2012.08.043

Cited by 9 publications

(21 citation statements)

References 31 publications

(38 reference statements)

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“…43 − 45 Low cooperativity PAM 12c (VU0405372) was ultimately identified and found to demonstrate a suitable balance of in vitro and in vivo properties for proof-of-concept studies in an amphetamine hyperlocomotor challenge model. In contrast to previously reported and related monocyclic ether series, 26 , 31 these bicyclic modulator scaffolds were overall found to exhibit narrow SAR, low efficacy, and have a higher propensity for pharmacological “mode switching” 15 upon chemical modification, demonstrating an SAR profile reminiscent of related acetylenic PAMs. 32 …”

Section: Introductioncontrasting

confidence: 91%

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Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu₅)

et al. 2014

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Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu5 PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu5 as well as antagonist activity at mGlu3. Structure–activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu5 PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.

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Section: Introductioncontrasting

confidence: 91%

“… Evolution of tetrahydronaphthyridine and dihydronaphthyridinone ether based mGlu 5 allosteric modulators ( 12 – 20 ) from nicotinamide 7 ( 26 ) and acetylenic modulator scaffold 11 . 32 …”

Section: Introductionmentioning

confidence: 99%

Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu₅)

et al. 2014

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“…Notably, L743V and the equivalent mutation in mGlu 1 were previously shown to enhance potentiation by PAMs (Knoflach et al, 2001;Muhlemann et al, 2006); however, for acetylene PAMs, L743V had no effect on cooperativity or affinity. Further studies are under way to probe interactions within the common allosteric site by modulators from distinct chemotypes to better inform our understanding of the molecular determinants of modulator affinity and cooperativity (Manka et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Probing the Metabotropic Glutamate Receptor 5 (mGlu₅) Positive Allosteric Modulator (PAM) Binding Pocket: Discovery of Point Mutations That Engender a “Molecular Switch” in PAM Pharmacology

et al. 2013

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Positive allosteric modulation of metabotropic glutamate receptor subtype 5 (mGlu 5 ) is a promising novel approach for the treatment of schizophrenia and cognitive disorders. Allosteric binding sites are topographically distinct from the endogenous ligand (orthosteric) binding site, allowing for co-occupation of a single receptor with the endogenous ligand and an allosteric modulator. Negative allosteric modulators (NAMs) inhibit and positive allosteric modulators (PAMs) enhance the affinity and/or efficacy of the orthosteric agonist. The molecular determinants that govern mGlu 5 modulator affinity versus cooperativity are not well understood. Focusing on the modulators based on the acetylene scaffold, we sought to determine the molecular interactions that contribute to PAM versus NAM pharmacology. Generation of a comparative model of the transmembrane-spanning region of mGlu 5 served as a tool to predict and interpret the impact of mutations in this region. Application of an operational model of allosterism allowed for determination of PAM and NAM affinity estimates at receptor constructs that possessed no detectable radioligand binding as well as delineation of effects on affinity versus cooperativity. Novel mutations within the transmembrane domain (TM) regions were identified that had differential effects on acetylene PAMs versus 2-methyl-6-(phenylethynyl)-pyridine, a prototypical NAM. Three conserved amino acids (Y658, T780, and S808) and two nonconserved residues (P654 and A809) were identified as key determinants of PAM activity. Interestingly, we identified two point mutations in TMs 6 and 7 that, when mutated, engender a mode switch in the pharmacology of certain PAMs.

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“…Selectivity was observed for 60 relative to known mGlu receptors. Poor solubility and metabolic stability prevented 60 from being evaluated in vivo [81]. The series in general was characterized by shallow SAR and so far has not yielded a NAM.…”

Section: Alkyne Replacementsmentioning

confidence: 98%

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

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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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Optimization of an ether series of mGlu5 positive allosteric modulators: Molecular determinants of MPEP-site interaction crossover

Cited by 9 publications

References 31 publications

Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu₅)

Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu₅)

Probing the Metabotropic Glutamate Receptor 5 (mGlu₅) Positive Allosteric Modulator (PAM) Binding Pocket: Discovery of Point Mutations That Engender a “Molecular Switch” in PAM Pharmacology

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

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Optimization of an ether series of mGlu5 positive allosteric modulators: Molecular determinants of MPEP-site interaction crossover

Cited by 9 publications

References 31 publications

Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu5)

Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu5)

Probing the Metabotropic Glutamate Receptor 5 (mGlu5) Positive Allosteric Modulator (PAM) Binding Pocket: Discovery of Point Mutations That Engender a “Molecular Switch” in PAM Pharmacology

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

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Product

Resources

About

Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu₅)

Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu₅)

Probing the Metabotropic Glutamate Receptor 5 (mGlu₅) Positive Allosteric Modulator (PAM) Binding Pocket: Discovery of Point Mutations That Engender a “Molecular Switch” in PAM Pharmacology