Seifert, Roland and Dove, Stefan (2009) Functional Selectivity of GPCR Ligand Stereoisomers: New Pharmacological Opportunities. Mol. Pharmacol. 75 (1), pp. 13-18.
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It is now well established that any given ligand for a G-protein coupled receptor (GPCR) does not simply possess a single defined efficacy. Rather, a ligand possesses multiple efficacies, depending on the specific down-stream signal transduction pathway analyzed. This diversity may be based on ligand-specific GPCR conformations and is often referred to as “Functional Selectivity”. It has been known for a century that stereoisomers of catecholamines differ in their potency, and in some systems, also in their efficacy. However, the molecular basis for efficacy differences of GPCR ligand stereoisomers has remained poorly defined. In an elegant study published in this issue of Molecular Pharmacology, Woo et al. show that stereosiomers of the b2-adrenoceptor-selective agonist fenoterol differentially activate Gs- and Gi-proteins in native rat cardiomyocytes. This study is so important because it is the first report to show that even the subtle structural differences within a ligand stereoisomer pair are sufficient to discriminate between GPCR conformations with distinct G-protein coupling properties. The study highlights of how important it is to examine the “more active” (eutomer) and the “less active” (distomer) stereoisomer to understand the mechanisms of action and the cellular effects of GPCR ligands. The study by the Xiao group will ignite a renaissance of the analysis of ligand stereoisomers, using sensitive pharmacological and biophysical assays. The available literature supports the notion that meticulous analysis of ligand stereoisomers is a goldmine for understanding mechanisms of GPCR activation, analysis of signal transduction pathways, development of new therapies for important diseases and drug safety.
|Institutions:|| Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann formerly Prof. Seifert)
|Projects:||GRK 760, Graduiertenkolleg Medizinische Chemie|
|Subjects:||500 Science > 570 Life sciences|
500 Science > 540 Chemistry & allied sciences
600 Technology > 610 Medical sciences Medicine
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Yes|
|Owner:||Prof. Dr. Stefan Dove|
|Deposited On:||20 Jan 2009 14:04|
|Last Modified:||05 Aug 2009 13:50|