Reassessment of the pharmacology of Sphingosine-1-phosphate S1P3 receptor ligands using the DiscoveRx PathHunter™ and Ca2+ release functional assays.

British Journal of Pharmacology
D M RiddyM R Dowling

Abstract

DiscoverRx's PathHunter™ assay measures GPCR agonist potency, via the recruitment of β-arrestin, independent of the subtype of G(α) protein activated. This assay is frequently used in drug discovery although little is known about the agonist pharmacology generated. Here we have compared agonist potency, efficacy and affinity values obtained in PathHunter™ assays with those from more established radioligand binding and functional techniques. Using cells expressing the human sphingosine-1-phosphate S1P(3) receptor at four different densities, we compared pharmacological affinity and efficacy values of four structurally distinct ligands - FTY720-P, VPC24191, CYM5442 and the endogenous agonist S1P - obtained from competition binding, functional Ca(2+) release and PathHunter™ assays. The pK(i) values for S1P were significantly different (9.34 ± 0.10 and 8.92 ± 0.15) in clones expressing different receptor levels using the binding assay. In the PathHunter™ and Ca(2+) assays, S1P and CYM5442 were full agonists, FTY720-P was a partial agonist, while the efficacy of VPC24191 could not be detected in PathHunter™ assays. VPC23019, previously described as a S1P(1/3) receptor antagonist, behaved as an S1P(3) receptor partial agonist in the ...Continue Reading

References

Oct 1, 1985·Analytical Biochemistry·P K SmithD C Klenk
Dec 22, 1983·Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character·J W Black, P Leff
Mar 1, 1995·Trends in Pharmacological Sciences·P Leff
Apr 23, 2002·The Journal of Biological Chemistry·Volker BrinkmannKevin R Lynch
May 3, 2003·Nature Reviews. Molecular Cell Biology·Sarah Spiegel, Sheldon Milstien
Dec 14, 2004·The Journal of Biological Chemistry·Michael D DavisKevin R Lynch
Mar 23, 2005·Gene·Gill HoldsworthGraeme Milligan
Jun 22, 2005·Proceedings of the National Academy of Sciences of the United States of America·Yasuhiro GonHugh Rosen
Jan 30, 2007·Journal of Biomolecular Screening·Clare M Scaramellini CarterSteven J Charlton
Jul 24, 2007·Trends in Pharmacological Sciences·Jonathan D Violin, Robert J Lefkowitz
Jan 4, 2008·The Journal of Investigative Dermatology·Karin LichteDagmar Meyer zu Heringdorf
Nov 28, 2008·Journal of Biomolecular Screening·Miranda M C van Der LeeGuido J R Zaman
Mar 21, 2009·Nature Reviews. Drug Discovery·David Marsolais, Hugh Rosen
Nov 9, 2011·British Journal of Pharmacology·Stephen P H AlexanderJohn A Peters

❮ Previous
Next ❯

Citations

Jul 6, 2014·Journal of Medicinal Chemistry·Alfonso CarotenutoPaolo Grieco
Jan 29, 2013·British Journal of Pharmacology·S NijmeijerR Leurs
Mar 20, 2014·British Journal of Pharmacology·David A SykesSteven J Charlton
Nov 12, 2017·Pharmacology & Therapeutics·Andrea Huwiler, Uwe Zangemeister-Wittke
Jun 11, 2016·Biochemical and Biophysical Research Communications·M TölleM Schuchardt

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.