Biopterin Analogues: Novel Nitric Oxide Synthase Inhibitors with Immunosuppressive Action

Authors: Werner E.R.; Werner-Felmayer G.

Source: Current Drug Metabolism, Volume 3, Number 2, April 2002 , pp. 119-121(3)

Publisher: Bentham Science Publishers

Abstract:

Tetrahydrobiopterin plays an essential role in nitric oxide synthase catalysis, not only as an allosteric modulator but also as a cofactor involved in electron flow through the enzyme. In absence of tetrahydrobiopterin, all isoforms of nitric oxide synthases are virtually inactive. The present review focusses on attempts to inhibit nitric oxide synthase by biopterin analogues, and what is known about the pharmacological effects of these compounds. While several biopterin analogues are capable of inhibiting nitric oxide synthases, the 4-amino analogue of tetrahydrobiopterin (4-amino tetrahydrobiopterin) is the compound of which pharmacological actions in animals have been described. 4-Amino tetrahydrobiopterin inhibits all three isoforms of nitric oxide synthases in micromolar concentrations. In cultured cells and in aortic strips, a surprising selectivity of inhibition of the inducible isoform of nitric oxide synthases has been observed. When applied intramuscularly, 4-amino tetrahydrobiopterin spreads throughout the body within minutes, and is cleared with a half life of about an hour. A single bolus dose applied intravenously in a rat model of septic shock, saved the animals from the lethal effects of endotoxin. When applied three times a day intramuscularly in a murine model of cardiac allograft rejection, 4-amino tetrahydrobiopterin prolongs allograft survival as efficiently as high-dose cyclosporin A treatment does. Thus, 4-amino tetrahydrobiopterin is an effective immunosuppressant. The mechansim of its action is currently under investigation.

Keywords: Biopterin analogues; Nitric oxide synthase inhibitors; tetrahydrobiopterin; Pterin-based inhibitors; Nitric oxide synthases; 4-amino tetrahydrobiopterin

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389200024605118

Publication date: 2002-04-01

• Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
  
  In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.

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• In this Subject: Anatomy & Physiology ,  Pharmacology
• By this author: Werner E.R. ;  Werner-Felmayer G.

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