Novel Screening Paradigms for the Identification of Allosteric Modulators and/or Biased Ligands for Challenging G-Protein-Coupled Receptors

Schann, Stéphan; Neuville, Pascal; Bouvier, Michel

doi:10.1016/b978-0-12-800167-7.00018-3

Cited by 3 publications

(6 citation statements)

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“…Interestingly, this molecule 1 was previously reported by a team from Vanderbilt University as being inactive at 30 μM in a Gqi5 functional test (compound 1i in Supporting Information of ref 28), whereas it behaves as a full PAM in our chimeric Gi/Gq (GqTOP) assay. This illustrates the differences that can be measured depending on the in vitro model systems used 31 and underlines the importance of validating the compounds activity in animal models in the early steps of an optimization program.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery, Structure–Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4

et al. 2017

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The metabotropic glutamate receptor 4 (mGluR4) is an emerging target for the treatment of Parkinson's disease (PD). However, since the discovery of its therapeutic potential, no ligand has been successfully developed enough to be tested in the clinic. In the present paper, we report for the first time the medicinal chemistry efforts conducted around the pharmacological tool (-)-PHCCC. This work led to the identification of compound 40, a potent and selective mGluR4 positive allosteric modulator (PAM) with good water solubility and demonstrating consistent activity across validated preclinical rodent models of PD motor symptoms after intraperitoneal administration: haloperidol-induced catalepsy in mouse and the rat 6-hydroxydopamine (6-OHDA) lesion model. Moreover, we also describe the identification of compound 60 a close analogue of compound 40 with improved pharmacokinetic profile after oral administration. On the basis of its favorable and unique preclinical profile, compound 60 (PXT002331, now foliglurax) was nominated as a candidate for clinical development.

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Section: ■ Introductionmentioning

confidence: 99%

Discovery, Structure–Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4

et al. 2017

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“…Allostery in GPCRs is recognized as a major direction in GPCR drug discovery, and specific methods have been developed for discovery of small molecule PAMs and NAMs [91]. For example, allosteric modulation of the metabotropic glutamate receptor 5 (mGluR5, PAMs and NAMs [110]) and γ-aminobutyric acid receptor B (GABA B R, PAMs [108]) is being explored mainly for CNS disorders, and other allosteric modulators such as GLP-1R PAMs are intended for treating diabetes and other conditions [92–94].…”

Section: New Pharmacological Dimensionsmentioning

confidence: 99%

“…These approaches include fluorescence-based screens in cells or membranes [131], bioluminescence resonance energy transfer (BRET)-based biosensors [91], and label free drug discovery [133]. For example, the G protein α (energy donor) and γ (energy acceptor) subunits may be labeled with matched fluorescent proteins to achieve a BRET signal when activated by a GPCR [157].…”

Section: Novel Screening and Assay Approachesmentioning

confidence: 99%

New paradigms in GPCR drug discovery

Jacobson

2015

Biochemical Pharmacology

150

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G protein-coupled receptors (GPCRs) remain a major domain of pharmaceutical discovery. The discovery of GPCR lead compounds and their optimization are now structure-based, thanks to advances in X-ray crystallography, molecular modeling, protein engineering and biophysical techniques. In silico screening provides useful hit molecules. New pharmacological approaches to tuning the pleotropic action of GPCRs include: allosteric modulators, biased ligands, GPCR heterodimer-targeted compounds, manipulation of polypharmacology, receptor antibodies and tailoring of drug molecules to fit GPCR pharmacogenomics. Measurements of kinetics and drug efficacy are factors influencing clinical success. With the exception of inhibitors of GPCR kinases, targeting of intracellular GPCR signaling or receptor cycling for therapeutic purposes remains a futuristic concept. New assay approaches are more efficient and multidimensional: cell-based, label-free, fluorescence-based assays, and biosensors. Tailoring GPCR drugs to a patient’s genetic background is now being considered. Chemoinformatic tools can predict ADME-tox properties. New imaging technology visualizes drug action in vivo. Thus, there is reason to be optimistic that new technology for GPCR ligand discovery will help improve the current narrowing of the pharmaceutical pipeline.

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“…Other advances in screening technologies can also be integrated into affinity-based methods, and in keeping with the illustration of GPCR drug discovery for this example, multiple assay technologies are available now to interrogate not only antagonists and ago nists but also allosteric modulators and biased ligands (e.g., binding to only one conformational state). These assays can also be integrated together post-HTS to deconvolute the complexity of GPCR signaling [26]. The growth of antibody tar geting of conformational states of GPCRs also represents not only a drug discov ery opportunity but also the development of important new tools to characterize GPCR pharmacology [26].…”

Section: Lead Generation Should Be Complemented By Auxiliary Technolomentioning

confidence: 99%

“…These assays can also be integrated together post-HTS to deconvolute the complexity of GPCR signaling [26]. The growth of antibody tar geting of conformational states of GPCRs also represents not only a drug discov ery opportunity but also the development of important new tools to characterize GPCR pharmacology [26]. Thus, the modern lead generation chemistry also needs to be a technology "aficionado" and stay acutely aware of new and promis ing technologies.…”

Section: Lead Generation Should Be Complemented By Auxiliary Technolomentioning

confidence: 99%

Modern Lead Generation Strategies

Holenz

Brown

2016

Methods and Principles in Medicinal Chemistry

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Novel Screening Paradigms for the Identification of Allosteric Modulators and/or Biased Ligands for Challenging G-Protein-Coupled Receptors

Cited by 3 publications

References 50 publications

Discovery, Structure–Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4

Discovery, Structure–Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4

New paradigms in GPCR drug discovery

Modern Lead Generation Strategies

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