To identify structural elements regulating this function, we introduced reactive cysteines into the alpha 7 ligand-binding domain allowing us to bind sulfhydryl-reactive (SH) agonist analogs or control reagents onto specific positions in the ligand binding domain. We identified four alpha 7 mutants (S36C, L38C, W55C, and L119C) in which the tethering of the SH reagents blocked further acetylcholine-evoked activation of the receptor. However, selleckchem after selective

reaction with SH agonist analogs, the type II allosteric modulator N-(5-chloro-2,4-dimethoxyphenyl)-N ‘-(5-methyl-3-isoxazolyl-3-isoxazolyl)-urea (PNU-120596) could reactivate L119C and W55C mutants and receptors with a reduced or modified C-loop. Modified S36C and L38C mutants were insensitive to reactivation by PNU-120596, whether they were reacted with agonist analogs or alternative SH reagents. Molecular modeling showed that in the W55C and L119C mutants, the ammonium pharmacophore of the agonist analog methanethiosulfonate-ethyltrimethylammonium would be in a similar but nonidentical position underneath

the C-loop. The orientation assumed by the ligand tethered to 119C was approximately 3-fold more sensitive to PNU-120596 than the alternative pose at 55C. Our results support the hypothesis that a single ligand can bind within the receptor in different ways and, depending on the specific binding pose, may variously Dehydrogenase inhibitor promote activation or desensitization, or, alternatively, function as a competitive antagonist. This insight may provide

a new approach for drug development.”
“BACKGROUND\n\nBlack patients in the United States undergoing angiography for suspected coronary artery disease (CAD) have consistently been found to have less disease than whites. As the effects of hypertension are greater in blacks than whites, and hypertensive heart disease may mimic CAD and lead to catheterization, we examined the association between race and hypertension as an explanation for the disparities in angiographic CAD.\n\nMETHODS\n\nUsing an academic hospital’s institutional database, we studied patients undergoing first-time elective angiography from 2001 to 2008. Using multivariable logistic regression with data on patient demographics, CAD risk factors, and coronary stenoses, we compared rates of angiographic disease for blacks and whites, creating OICR-9429 nmr models separately for patients with and without hypertension. We then tested the significance of an interaction term between race and hypertension on angiographic findings.\n\nRESULTS\n\nWe identified 1,203 black and 2,538 white patients who underwent initial elective angiography. Black patients were less likely to have a significant stenotic lesion (>= 50% stenosis in the left main artery or >= 70% stenosis elsewhere) than whites (adjusted risk ratio 0.65; 95% confidence interval (Cl) 0.55-0.75). Among patients with hypertension this difference was exaggerated (adjusted risk ratio 0.60; 95% Cl 0.51-0.71).