2-phenyl-4-4-5-5-tetramethylimidazoline-1-oxyl-3-oxide has been researched along with pyrazolopyridine* in 1 studies
1 other study(ies) available for 2-phenyl-4-4-5-5-tetramethylimidazoline-1-oxyl-3-oxide and pyrazolopyridine
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NO-independent regulatory site on soluble guanylate cyclase.
Nitric oxide (NO) is a widespread, potent, biological mediator that has many physiological and pathophysiological roles. Research in the field of NO appears to have followed a straightforward path, and the findings have been progressive: NO and cyclic GMP are involved in vasodilatation; glycerol trinitrate relaxes vascular smooth muscles by bioconversion to NO; mammalian cells synthesize NO; and last, NO mediates vasodilatation by stimulating the soluble guanylate cyclase (sGC), a heterodimeric (alpha/beta) haem protein that converts GTP to cGMP2-4. Here we report the discovery of a regulatory site on sGC. Using photoaffinity labelling, we have identified the cysteine 238 and cysteine 243 region in the alpha1-subunit of sGC as the target for a new type of sGC stimulator. Moreover, we present a pyrazolopyridine, BAY 41-2272, that potently stimulates sGC through this site by a mechanism that is independent of NO. This results in antiplatelet activity, a strong decrease in blood pressure and an increase in survival in a low-NO rat model of hypertension, and as such may offer an approach for treating cardiovascular diseases. Topics: Amino Acid Sequence; Animals; Antihypertensive Agents; Binding Sites; Blood Pressure; Cyclic N-Oxides; Cysteine; Disease Models, Animal; Enzyme Activation; Female; Guanylate Cyclase; Heme; Humans; Imidazoles; In Vitro Techniques; Indazoles; Molecular Sequence Data; Nitric Oxide; Photoaffinity Labels; Platelet Aggregation Inhibitors; Pyrazoles; Pyridines; Rats; Solubility | 2001 |