Drugs that activate specific nitric oxide sensitive guanylyl cyclase isoforms independent of nitric oxide release.
Nitric oxide (NO) releasing drugs have helped patients suffering from angina pectoris for more than a century. In the 1970s NO-sensitive guanylyl cyclase was identified as the target of NO. Since then, three different isoforms of the enzyme have been identified. All NO-releasing drugs act by binding of NO to the prosthetic heme group common to all three isoforms. They thus act all as isoform-unspecific substances. This review addresses recently developed drugs that activate NO-sensitive guanylyl cyclase independent of NO-release. They have great potential in the treatment of angina pectoris, hypertension and erectile dysfunction. The molecular target has been validated by the successful clinical use of NO-releasing drugs for more than a century. At the same time the mode of action of these drugs is entirely new. The development of highly isoform-specific derivatives with distinct pharmacological profiles is now an open possibility with great potential.
Behrends
Sönke
S
Institute of Experimental and Clinical Pharmacology and Toxicology, University clinic Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. behrends@plexus.uke.uni-hamburg.de
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology / Q000627:therapeutic use; D005996:Nitroglycerin / Q000627:therapeutic use; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D005996:Nitroglycerin