Pterin antagonists

Amino-tetrahydrobiopteridin is a potent pterin antagonist of nitric oxide synthases. The essential pterin requirement for de novo synthesis of functionally intact iNOS renders it possible that this drug exhibits selectivity towads the inducible isoform of NOS in vivo (Pitters et al. 1997). 

Figure 10.1 also shows the structures of the folate antagonist methotrexate (iV -methyl aminopterin) and the pterin coenzymes tetrahydrobiopterin (Section 10.4) and molybdopterin (Section 10.5). 

On account of the requirement of NOS for tetrahy-drobiopterin, two general approaches toward a modulation of NOS activity seem feasible, manipulation of intracellular tetrahydrobiopterin levels and pterin-binding site antagonists. However, recombinant tetrahydrobiopterin-free NOS II catalysed the oxidation of four N-hydroxyguanidines tested by NADPH and O2, with formation of N02 and NOs" at rates between 20 and 80 nmol min" (mg of protein)" (Moali et al. 2001). In the case of N-(4-chlorophenyO-hT-hydroxyguanidine, formation of the corresponding urea and cyanamide was also detected besides that of N02" and NO3". These tetrahydrobiopterin-free NOS Il-dependent reactions were inhibited by modulators of electron transfer in NOS such as thiocitrulline or imidazole. 

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