Discovery of 1-Butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1<i>H</i>)-pyridone (JNJ-40411813): A Novel Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor

Cid, José M.; Tresadern, Gary; Duvey, Guillaume; Lütjens, Robert; Finn, Terry; Rocher, Jean‐Philippe; Poli, Sonia; Vega, Javier Martínez; Lucas, Ana I. De; Matesanz, Encarnación; Linares, María Lourdes; Andrés, Juvenal; Alcázar, Jesús; Alonso, J.M.; Macdonald, Gregor; Oehlrich, Daniel; Lavreysen, Hilde; Ahnaou, Abdelah; Drinkenburg, Wilhelmus; Mackie, Claire; Pype, Stefan; Gallacher, David J.; Trabanco, Andrés A.

doi:10.1021/jm500496m

Cited by 55 publications

(38 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…281 Although efficacy signals were met on some measures, the signal on the primary outcome measure was not significant, and the overall data did not support continued development of the compound in anxious depression. 278 …”

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

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

show abstract

“…Reference PAMs in the field include JNJ-40068782 [21], BINA [22] and JNJ-46281222 [23]. Two PAMs entered clinical trials, AZD8529 of AstraZeneca and JNJ-40411813 (also known as ADX71149) from Janssen/Addex [24][25][26][27][28][29]. A number of mGlu 2 negative allosteric modulators (NAMs) have been characterized in vivo, including a recent series of NAMs from Janssen and RO4491533 and decoglurant from Roche, of which the latter also advanced into clinical trials [30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Constitutive activity of the metabotropic glutamate receptor 2 explored with a whole-cell label-free biosensor

Doornbos

Linden

Vereyken

et al. 2018

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

Label-free cellular assays using a biosensor provide new opportunities for studying G protein-coupled receptor (GPCR) signaling. As opposed to conventional in vitro assays, integrated receptor-mediated cellular responses are determined in real-time rather than a single downstream signaling pathway. In this study, we examined the potential of a label-free whole cell impedance-based biosensor system (i.e. xCELLigence) to study the pharmacology of one GPCR in particular, the mGlu 2 receptor. This receptor is a target for the treatment of several psychiatric diseases such as schizophrenia and depression.After optimization of assay conditions to prevent interference of endogenous glutamate in the culture medium, detailed pharmacological assessments were performed. Concentration-response curves showed a concentration-dependent increase in impedance for agonists and positive allosteric modulators, whereas receptor inhibition by an antagonist or negative allosteric modulator resulted in a concentration-dependent decrease in cellular impedance. Interestingly, constitutive receptor activity was observed that was decreased by LY341495, which therefore behaved as an inverse agonist here, a property that was heretofore unappreciated. This was confirmed by concentration-dependent modulation of LY341495 potency and efficacy by a allosteric modulators.In summary, the use of the xCELLigence system to study mGlu 2 receptor pharmacology was validated. This is the first class C GPCR to be characterized extensively by such method, opening new avenues to study receptor pharmacology including inverse agonism and demonstrating its value for future drug discovery efforts of mGlu receptors as well as other GPCRs.

show abstract

“…JNJ‐40411813 (also known as ADX71149) from Janssen Pharmaceuticals and Addex Therapeutics failed to meet the criterion for efficacy signal in patients with major depressive disorder with significant anxiety symptoms. In contrast, in an exploratory phase 2a study in schizophrenia, not powered to determine statistical significance of effects rather a signal generation study, JNJ‐40411813 met the primary objectives of safety and tolerability and also demonstrated an effect in patients with residual negative symptoms (Cid et al , ).…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism of positive allosteric modulation of the metabotropic glutamate receptor 2 by JNJ‐46281222

Doornbos

Pérez‐Benito

Tresadern³

et al. 2016

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

BACKGROUND AND PURPOSEAllosteric modulation of the mGlu 2 receptor is a potential strategy for treatment of various neurological and psychiatric disorders. Here, we describe the in vitro characterization of the mGlu 2 positive allosteric modulator (PAM) JNJ-46281222 and its radiolabelled counterpart [3 H]-JNJ-46281222. Using this novel tool, we also describe the allosteric effect of orthosteric glutamate binding and the presence of a bound G protein on PAM binding and use computational approaches to further investigate the binding mode. EXPERIMENTAL APPROACHWe have used radioligand binding studies, functional assays, site-directed mutagenesis, homology modelling and molecular dynamics to study the binding of JNJ-46281222. KEY RESULTSJNJ-46281222 is an mGlu 2 -selective, highly potent PAM with nanomolar affinity (K D = 1.7 nM). Binding of CONCLUSION AND IMPLICATIONSOur results obtained with JNJ-46281222 in unlabelled and tritiated form further contribute to our understanding of mGlu 2 allosteric modulation. The computational simulations and mutagenesis provide a plausible binding mode with indications of how the ligand permits allosteric activation. This study is therefore of interest for mGlu 2 and class C receptor drug discovery.

show abstract

Discovery of 1-Butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone (JNJ-40411813): A Novel Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor

Cited by 55 publications

References 38 publications

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

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

Constitutive activity of the metabotropic glutamate receptor 2 explored with a whole-cell label-free biosensor

Molecular mechanism of positive allosteric modulation of the metabotropic glutamate receptor 2 by JNJ‐46281222

Contact Info

Product

Resources

About