| Allosteric modulation of G protein-coupled receptors: a pharmacological perspective. | |
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MedLine Citation:
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PMID: 20637785 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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G protein-coupled receptor (GPCR)-based drug discovery has traditionally focused on targeting the orthosteric site for the endogenous agonist. However, many GPCRs possess allosteric sites that offer enormous potential for greater selectivity in drug action. The complex behaviors ascribed to allosteric ligands also present challenges to those interested in preclinical lead discovery. These challenges include the need to detect and quantify various phenomena when screening for allosteric ligands, such as saturability of effect, probe dependence, differential effects on orthosteric ligand affinity vs. efficacy, system-dependent allosteric agonism, stimulus-bias (functional selectivity), and the potential existence of bitopic (hybrid orthosteric/allosteric) ligands. These issues are also critical when interpreting structure-function studies of allosteric GPCR modulators because mutations in receptor structure, either engineered or naturally occurring, can differentially affect not only modulator affinity, but also the nature, magnitude and direction of the allosteric effect on orthosteric ligand function. The ever-expanding array of allosteric modulators arising from both academic and industrial research also highlights the need for the development of a uniform approach to nomenclature of such compounds. |
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Authors:
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Peter Keov; Patrick M Sexton; Arthur Christopoulos |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-15 |
Journal Detail:
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Title: Neuropharmacology Volume: 60 ISSN: 1873-7064 ISO Abbreviation: Neuropharmacology Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-11-15 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0236217 Medline TA: Neuropharmacology Country: England |
Other Details:
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Languages: eng Pagination: 24-35 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Ltd. All rights reserved. |
Affiliation:
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Monash Institute of Pharmaceutical Sciences & Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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