Biopterin analogues: novel nitric oxide synthase inhibitors with immunosuppressive action.

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 focuses 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 mechanism of its action is currently under investigation.