Mechanism of Corticotropin-Releasing Factor Type I Receptor Regulation by Nonpeptide Antagonists

Hoare, Sam R.J.; Sullivan, Sue; Ling, Nicholas; Crowe, Paul D.; Grigoriadis, Dimitri E.

doi:10.1124/mol.63.3.751

Cited by 69 publications

(100 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Cell membrane fractions were prepared as previously described (Hoare et al, 2003) and resuspended in 50 mM HEPES, 10 mM MgCl 2 , 100 mM NaCl, and 1 mM CaCl 2 , pH 7.2 for use in competitive radioligand binding reactions. Reactions were performed in duplicate and consisted of 25-l unlabeled chemokine (R&D Systems Inc., Minneapolis, MN) at indicated concentrations, 25-l radiolabeled chemokine ligand (ϳ70 nM; [ 125 I]CXCL11 and [ 125 I]CXCL10 with specific activities of 1500 and 2200 Ci/mmol, respectively; PerkinElmer Life and Analytical Sciences, Boston, MA), and 50-l membrane protein (5 g) added sequentially in assay buffer (50 mM HEPES, 10 mM MgCl 2 , 100 mM NaCl, 1 mM CaCl 2 , and 0.1% BSA, pH 7.2) to low-binding 96-well plates (Corning, Acton, MA).…”

Section: Methodsmentioning

confidence: 99%

Pharmacological Characterization of CXC Chemokine Receptor 3 Ligands and a Small Molecule Antagonist

Heise¹,

Pahuja²,

Hudson³

et al. 2005

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The CXC chemokine receptor 3 (CXCR3) is predominantly expressed on T helper type 1 (Th1) cells that are involved in inflammatory diseases. The three CXCR3 ligands CXCL9, CXCL10, and CXCL11 are produced at sites of inflammation and elicit migration of pathological Th1 cells. Here, we are the first to characterize the pharmacological potencies and specificity of a CXCR3 antagonist, N-1R- [3-(4-ethoxy-phenyl of 7 to 18 nM). NBI-74330 was selective for CXCR3 because it showed no significant inhibition of chemotactic responses to other chemokines and did not inhibit radioligand binding to a panel of nonchemokine G-protein coupled receptors. There was a striking difference in potencies among the three CXCR3 ligands, with CXCL11 Ͼ Ͼ CXCL10 Ͼ CXCL9. A comparison of the rank order of K i values with the rank order of monocyte production levels of these three ligands revealed a precise inverse correlation, suggesting that the weaker receptor affinities of CXCL9 and CXCL10 were physiologically compensated for by an elevated expression, perhaps to maintain effectiveness of each ligand under physiological conditions.

show abstract

Section: Methodsmentioning

confidence: 99%

Pharmacological Characterization of CXC Chemokine Receptor 3 Ligands and a Small Molecule Antagonist

Heise¹,

Pahuja²,

Hudson³

et al. 2005

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…We did not see evidence of radiolabeled metabolites in brain with these radioligands, at least to the degree that the time-activity curves did not evidence differential retention of any radiolabeled molecule. As well, release of endogenous ligand, in this case CRF, may alter binding and dissociation of nonpeptide antagonists for CRF1 [49]. Therefore, a stress response in the baboons due to preparation for PET imaging might be of particular relevance for detection of CRF1 given the receptor's central role in the stress response system.…”

Section: Discussionmentioning

confidence: 99%

PET Imaging of CRF1 with [11C]R121920 and [11C]DMP696: is the target of sufficient density?

Sullivan

Parsey

Kumar

et al. 2007

Nuclear Medicine and Biology

View full text Add to dashboard Cite

Aim-Overstimulation of the CRF type 1 receptor (CRF1) is implicated in anxiety and depressive disorders. The aim of this study was to investigate the in vivo binding characteristics of [ 11 C]R121920 and [ 11 C]DMP696 in the non-human primate for application in positron emission tomography (PET) studies of CRF1.Methods-PET imaging with the two novel CRF1 radioligands was performed in baboon. In vitro binding studies for CRF1 were performed in postmortem brain tissue of baboon and human to assess sufficiency of receptor density for PET.Results-Both [ 11 C]R121920 and [ 11 C]DMP696 distributed rapidly and uniformly throughout brain. Washout was comparable across brain regions, without differences in volume of distribution between regions reported to have high and low in vitro CRF1 binding. Membrane-enriched tissue homogenate assay using [ 125 I]Tyr 0 -sauvagine and specific CRF1 antagonists CP154,526 and SN003 in human occipital cortex yielded maximal binding (B max ) of 63.3 and 147.3 fmol/mg protein, respectively, and in human cerebellar cortex yielded B max of 103.6 and 64.6 fmol/mg protein, respectively. Dissociation constants (K D ) were subnanomolar. In baboon, specific binding was not detectable in the same regions; therefore B max and K D were not measurable. Autoradiographic results were consistent except there was also detectable CRF1-specific binding in baboon cerebellum. Conclusion-Neither[ 11 C]R121920 nor [ 11 C]DMP696 demonstrated quantifiable regional binding in vivo in baboon. In vitro results suggest CRF1 density in baboon may be insufficient for PET. Studies in man may generate more promising results due to the higher CRF1 density compared with baboon in cerebral cortex and cerebellum.

show abstract

“…GPCRs are prime drug targets and it is estimated that greater than 40 % of all modern marketed drugs target GPCRs (Moro et al 2005). The CRH receptor (CRHR) is a GPCR belonging to the class B or secretin family ( Figure 2) (Bale and Vale 2004;Dautzenberg and Hauger 2002;Hoare et al 2003;Hoare 2005). Three subtypes of CRHRs have been identified.…”

Section: The Crh Receptor and Its Ligands 131 The Crhr: Structure mentioning

confidence: 99%

Biomimetic screening of class B G protein-coupled receptors

et al. 2011

View full text Add to dashboard Cite

Mechanism of Corticotropin-Releasing Factor Type I Receptor Regulation by Nonpeptide Antagonists

Cited by 69 publications

References 31 publications

Pharmacological Characterization of CXC Chemokine Receptor 3 Ligands and a Small Molecule Antagonist

Pharmacological Characterization of CXC Chemokine Receptor 3 Ligands and a Small Molecule Antagonist

PET Imaging of CRF1 with [11C]R121920 and [11C]DMP696: is the target of sufficient density?

Biomimetic screening of class B G protein-coupled receptors

Contact Info

Product

Resources

About