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Open Access Research article

NO-independent regulatory site of direct sGC stimulators like YC-1 and BAY 41-2272

Eva Maria Becker1, Cristina Alonso-Alija1, Heiner Apeler1, Rupert Gerzer3, Torsten Minuth1, Ulrich Pleiβ1, Peter Schmidt1, Matthias Schramm1, Henning Schröder2, Werner Schroeder1, Wolfram Steinke1, Alexander Straub1 and Johannes-Peter Stasch1*

Author Affiliations

1 Pharma Research Center, Bayer AG, Wuppertal, Germany

2 Martin Luther University, School of Pharmacy, Halle, Germany

3 DLR, Institute of Aerospace Medicine, Köln, Germany

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BMC Pharmacology 2001, 1:13  doi:10.1186/1471-2210-1-13

Published: 28 December 2001



The most important receptor for nitic oxide is the soluble guanylate cyclase (sGC), a heme containing heterodimer. Recently, a pyrazolopyridine derivative BAY 41-2272, structurally related to YC-1, was identified stimulating soluble guanylate cyclase in an NO-independent manner, which results in vasodilatation and antiplatelet activity. The study described here addresses the identification of the NO-independent site on soluble guanylate cyclase.


We developed a photoaffinity label (3H-meta-PAL) for the direct and NO-independent soluble guanylate cyclase (sGC) stimulator BAY 41-2272 by introducing an azido-group into the tritium labeled compound. The synthesized photoaffinitylabel directly stimulates the purified sGC and shows in combination with NO a synergistic effect on sGC activity. Irradiation with UV light of 3H-meta-PAL together with the highly purified sGC leads to a covalent binding to the α1-subunit of the enzyme. This binding is blocked by unlabeled meta-PAL, YC-1 and BAY 41-2272. For further identification of the NO-independent regulatory site the 3H-meta-PAL labeled sGC was fragmented by CNBr digest. The 3H-meta-PAL binds to a CNBr fragment, consisting of the amino acids 236–290 of the α1-subunit. Determination of radioactivity of the single PTH-cycles from the sequencing of this CNBr fragment detected the cysteines 238 and 243 as binding residues of the 3H-meta-PAL.


Our data demonstrate that the region surrounding the cysteines 238 and 243 in the α1-subunit of the sGC could play an important role in regulation of sGC activity and could be the target of this new type of sGC stimulators.