Rational design of dualsteric GPCR ligands: quests and promise

Dualsteric ligands represent a novel mode of targeting G protein‐coupled receptors (GPCRs). These compounds attach simultaneously to both, the orthosteric transmitter binding site and an additional allosteric binding area of a receptor protein. This approach allows the exploitation of favourable cha...

Full description

Saved in:
Bibliographic Details
Published inBritish journal of pharmacology Vol. 159; no. 5; pp. 997 - 1008
Main Authors Mohr, Klaus, Tränkle, Christian, Kostenis, Evi, Barocelli, Elisabetta, De Amici, Marco, Holzgrabe, Ulrike
Format Journal Article
LanguageEnglish
Published Oxford, UK Blackwell Publishing Ltd 01.03.2010
Subjects
allosteric
Allosteric Site
Animals
Binding Sites
bitopic
Drug Delivery Systems
Drug Design
dualsteric
functional selectivity
G protein‐coupled receptors
Humans
Ligands
multivalent
muscarinic acetylcholine receptor
orthosteric
Protein Binding
Receptors, G-Protein-Coupled - drug effects
Receptors, G-Protein-Coupled - metabolism
subtype selectivity
Themed Section: Reviews
Online AccessGet full text

Cover

More Information
Summary:Dualsteric ligands represent a novel mode of targeting G protein‐coupled receptors (GPCRs). These compounds attach simultaneously to both, the orthosteric transmitter binding site and an additional allosteric binding area of a receptor protein. This approach allows the exploitation of favourable characteristics of the orthosteric and the allosteric site by a single ligand molecule. The orthosteric interaction provides high affinity binding and activation of receptors. The allosteric interaction yields receptor subtype‐selectivity and, in addition, may modulate both, efficacy and intracellular signalling pathway activation. Insight into the spatial arrangement of the orthosteric and the allosteric site is far advanced in the muscarinic acetylcholine receptor, and the design of dualsteric muscarinic agonists has now been accomplished. Using the muscarinic receptor as a paradigm, this review summarizes the way from suggestive evidence for an orthosteric/allosteric overlap binding to the rational design and experimental validation of dualsteric ligands. As allosteric interactions are increasingly described for GPCRs and as insight into the spatial geometry of ligand/GPCR‐complexes is growing impressively, the rational design of dualsteric drugs is a promising new approach to achieve fine‐tuned GPCR‐modulation. This article is part of a themed section on Molecular Pharmacology of GPCR. To view the editorial for this themed section visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00695.x
ISSN:0007-1188
1476-5381
DOI:10.1111/j.1476-5381.2009.00601.x