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Review ArticleReview Article

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Stephan Urwyler
David R. Sibley, ASSOCIATE EDITOR
Pharmacological Reviews March 2011, 63 (1) 59-126; DOI: https://doi.org/10.1124/pr.109.002501
Stephan Urwyler
Department of Chemistry and Biochemistry, University of Berne, Berne, Switzerland
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David R. Sibley
Department of Chemistry and Biochemistry, University of Berne, Berne, Switzerland
Roles: ASSOCIATE EDITOR
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Abstract

Allosteric receptor modulation is an attractive concept in drug targeting because it offers important potential advantages over conventional orthosteric agonism or antagonism. Allosteric ligands modulate receptor function by binding to a site distinct from the recognition site for the endogenous agonist. They often have no effect on their own and therefore act only in conjunction with physiological receptor activation. This article reviews the current status of allosteric modulation at family C G-protein coupled receptors in the light of their specific structural features on the one hand and current concepts in receptor theory on the other hand. Family C G-protein-coupled receptors are characterized by a large extracellular domain containing the orthosteric agonist binding site known as the “venus flytrap module” because of its bilobal structure and the dynamics of its activation mechanism. Mutational analysis and chimeric constructs have revealed that allosteric modulators of the calcium-sensing, metabotropic glutamate and GABAB receptors bind to the seven transmembrane domain, through which they modify signal transduction after receptor activation. This is in contrast to taste-enhancing molecules, which bind to different parts of sweet and umami receptors. The complexity of interactions between orthosteric and allosteric ligands is revealed by a number of adequate biochemical and electrophysiological assay systems. Many allosteric family C GPCR modulators show in vivo efficacy in behavioral models for a variety of clinical indications. The positive allosteric calcium sensing receptor modulator cinacalcet is the first drug of this type to enter the market and therefore provides proof of principle in humans.

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  • This article is available online at http://pharmrev.aspetjournals.org.

    doi:10.1124/pr.109.002501.

  • © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 63 (1)
Pharmacological Reviews
Vol. 63, Issue 1
1 Mar 2011
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Review ArticleReview Article

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Stephan Urwyler
Pharmacological Reviews March 1, 2011, 63 (1) 59-126; DOI: https://doi.org/10.1124/pr.109.002501

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Review ArticleReview Article

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Stephan Urwyler
Pharmacological Reviews March 1, 2011, 63 (1) 59-126; DOI: https://doi.org/10.1124/pr.109.002501
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  • Article
    • Abstract
    • I. Introduction
    • II. Allosteric Ligands for Taste Receptors: Not Only the Proof of Concept
    • III. Allosteric Modulators Allow for Subtype Selectivity among Multiple Metabotropic Glutamate Receptors
    • IV. GABAB Receptor Function Involves Allosteric Interactions across a Heterodimer
    • V. Allosteric Modulators of the Calcium-Sensing Receptor: the First Clinical Success
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