International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the Nomenclature of Receptor Allosterism and Allosteric Ligands

Christopoulos, Arthur; Changeux, Jean Pierre; Catterall, William A.; Fabbro, Doriano; Burris, Thomas P.; Cidlowski, John A.; Olsen, Richard W.; Peters, John A.; Neubig, Richard R.; Pin, Jean‐Philippe; Sexton, Patrick M.; Kenakin, Terry; Ehlert, Frederick J.; Spedding, Michael; Langmead, Christopher J.

doi:10.1124/pr.114.008862

Cited by 195 publications

(219 citation statements)

References 303 publications

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“…3C). Notably, β1 had a profile similar to α5, a previously reported monobody directed to mouse GPR56, in that both bound the full ECR but not the isolated GAIN or PLL domain, and functioned as an allosteric inverse agonist of G-protein signaling (36,38). In contrast to β1, β7 that targeted the PLL domain increased signaling of hGPR56 with EC 50 of 800 ± 500 nM, resulting in a ∼1.6-fold increase in signaling relative to basal activity (Fig.…”

Section: Resultsmentioning

confidence: 76%

“…In contrast to β1, β7 that targeted the PLL domain increased signaling of hGPR56 with EC 50 of 800 ± 500 nM, resulting in a ∼1.6-fold increase in signaling relative to basal activity (Fig. 3C), and thus, may be classified as an allosteric agonist of G-protein signaling (38). The effect of β7 was also specific to human GPR56 ( Fig.…”

Section: Resultsmentioning

confidence: 96%

“…Rather than direct interactions, colored arrows represent regulation of 7TM signaling by the ECR or monobodies. Designations of "allosteric inverse agonist," "neutral allosteric ligand," and "allosteric agonist" are based on definitions proposed by Christopoulos et al (38).…”

Section: Methodsmentioning

confidence: 99%

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Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Salzman

Zhang

Gupta

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

105

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Adhesion G protein-coupled receptors (aGPCRs) play critical roles in diverse biological processes, including neurodevelopment and cancer progression. aGPCRs are characterized by large and diverse extracellular regions (ECRs) that are autoproteolytically cleaved from their membrane-embedded signaling domains. Although ECRs regulate receptor function, it is not clear whether ECRs play a direct regulatory role in G-protein signaling or simply serve as a protective cap for the activating "Stachel" sequence. Here, we present a mechanistic analysis of ECR-mediated regulation of GPR56/ADGRG1, an aGPCR with two domains [pentraxin and laminin/neurexin/sex hormonebinding globulin-like (PLL) and G protein-coupled receptor autoproteolysis-inducing (GAIN)] in its ECR. We generated a panel of high-affinity monobodies directed to each of these domains, from which we identified activators and inhibitors of GPR56-mediated signaling. Surprisingly, these synthetic ligands modulated signaling of a GPR56 mutant defective in autoproteolysis and hence, in Stachel peptide exposure. These results provide compelling support for a ligandinduced and ECR-mediated mechanism that regulates aGPCR signaling in a transient and reversible manner, which occurs in addition to the Stachel-mediated activation.adhesion GPCR | allostery | cell signaling | monobody | protein engineering

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Section: Resultsmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 96%

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Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Salzman

Zhang

Gupta

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

105

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“…was achieved in a good yield, through coupling of commercially available 1H-indole-2-carboxylic acid (2) 2 NH, NaBH(OAc) 3 , 1,2-dichloroethane, rt, 50-56%; in the case of 7a, the product was converted to the corresponding HCl salt form using 1 M HCl/Et 2 O (e) TFA/DCM (1:3), rt, 96-99%; (f) DIPEA, BOP, DCM, 36-49%; in the case of 9a, the product was converted to the corresponding HCl salt form using 1 M HCl (aq) .…”

Section: Chemistry the Synthesis Of The Smallest Fragment Of 1 N-ismentioning

confidence: 99%

“…1 There has been an increasing interest in targeting allosteric sites within these proteins (sites that are topographically distinct from the orthosteric binding site of the endogenous hormone or neurotransmitter) to achieve greater selectivity across receptor subtypes. 2 More recently, bitopic ligands, i.e. molecules in which orthosteric and allosteric pharmacophores have been linked together, have emerged as a new approach to develop selective GPCR ligands.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D₂ Receptor Through Fragmentation of a Bitopic Ligand

et al. 2015

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(2015) Discovery of a novel class of negative allosteric modulator of the dopamine D2 receptor through fragmentation of a bitopic ligand. Journal of Medicinal Chemistry, 58 (17). pp. 6819-6843. ISSN 0022-2623 Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/30315/1/jm-2015-005859.R2%20-%20JMC %2058%2817%29%202015%206819.pdf Copyright and reuse:The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. This article is made available under the University of Nottingham End User licence and may be reused according to the conditions of the licence. For more details see: http://eprints.nottingham.ac.uk/end_user_agreement.pdf A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ABSTRACT Recently, we have demonstrated that N- ((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H) 'allosteric lead', we designed and synthesised an extensive fragment library to generate novel SAR and identify N-butyl-1H-indole-2-carboxamide (11d), which displayed both increased negative cooperativity and affinity for the D 2 R. These data illustrate that fragmentation of extended compounds can expose fragments with purely allosteric pharmacology.

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Novel Strategies Targeting G ‐Protein‐Coupled Receptors: An Overview

García‐Cárceles

2018

Encyclopedia of Life Sciences

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G‐protein‐coupled receptors (GPCRs) represent the largest group of cell surface receptors encoded by the human genome (∼2%) and have been associated to a multitude of human disorders, which makes them the focus of attention of many drug discovery programs. Traditionally, the development of drugs that target GPCRs has been focused on finding agonists or antagonists that displace the natural or endogenous ligand to activate or inhibit the receptor. Emerging knowledge of structure and physiological functions of GPCRs has begun to alter the approaches to drug discovery. Thus, over the past two decades, novel strategies such as the development of biased and bitopic ligands, allosteric modulators, pepducins or ligands targeting GPCR heteromers have appeared. Some of these new approaches have proved to be productive, yielding molecules currently in clinical trials or even marketed. Key Concepts GPCRs are cell membrane proteins essential for the survival of eukaryotic cells and they can be classified in four different classes based on their amino acid sequence. GPCRs are responsible for the realisation of cell functions through the transduction of a wide range of extracellular stimuli such as light, hormones, odours, peptides and neurotransmitters among others. GPCRs are associated with a multitude of human disorders, in fact, medicines targeting these receptors comprise 35% of the drugs on the market. Traditional approaches targeting GPCRs, that is development of agonists or antagonists that compete with the orthosteric or endogenous ligand, have become ineffective developing new drugs. Selectivity across subtypes in a certain receptor family has been the major issue in order to obtain safer drugs. The emergence of new and more sensitive pharmacological, biochemical and biophysical techniques have helped in designing novel strategies targeting GPCRs. The publication of crystal structures of GPCRs bound to various kind of ligands have been particularly helpful in determining the molecular basis of ligand binding.

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International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the Nomenclature of Receptor Allosterism and Allosteric Ligands

Cited by 195 publications

References 303 publications

Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D₂ Receptor Through Fragmentation of a Bitopic Ligand

Novel Strategies Targeting G ‐Protein‐Coupled Receptors: An Overview

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International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the Nomenclature of Receptor Allosterism and Allosteric Ligands

Cited by 195 publications

References 303 publications

Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand

Novel Strategies Targeting G ‐Protein‐Coupled Receptors: An Overview

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Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D₂ Receptor Through Fragmentation of a Bitopic Ligand