1 7‐Nitro indazole (7‐NI) produces potent inhibition of rat cerebellar nitric oxide synthase (NOS) with an IC50 of 0.9 ± 0.1 μm (n = 6). NOS activity is dependent on the presence of both exogenous CaCl2 and NADPH. The inhibitory potency of 7‐NI remained unaltered in the presence of different concentrations of either CaCl2 (0.75–7.5 mm) or NADPH (0.05–5.0 mm). 2 Kinetic (Lineweaver‐Burke) analysis of the effect of 7‐NI on rat cerebellar NOS revealed that inhibition was of a competitive nature with a Ki value of 5.6 μm. The Km of cerebellar NOS with respect to L‐arginine was 2.5 μm. 3 The following indazole derivatives (IC50 values shown in parentheses, all n = 6) caused concentration‐related inhibition of rat cerebellar NOS in vitro: 6‐nitro indazole (31.6 ± 3.4 μm), 5‐nitro indazole (47.3 ± 2.3 μm), 3‐chloro indazole (100.0 ± 5.5 μm), 3‐chloro 5‐nitro indazole (158.4 ± 2.1 μm) and indazole (177.8 ± 2.1 μm). The IC50 values for 5‐amino indazole, 6‐amino indazole and 6‐sulphanilimido indazole were in excess of 1 mm; 3‐indazolinone was inactive. 4 7‐NI (10 mg kg−1) administered i.p. to rats produced 60 min thereafter a significant inhibition of NOS activity in cerebellum (31.1 ± 3.2%, n = 6), cerebral cortex (38.2 ± 5.6%, n = 6), hippocampus (37.0 ± 2.8%, n = 6) and adrenal gland (23.7 ± 3.0%, n = 6). NOS activity in olfactory bulb and stomach fundus were unchanged. 5 These results indicate that 7‐NI is a potent and competitive inhibitor of rat brain NOS in vitro and also inhibits NOS in different brain regions and in the adrenal gland in vivo. Inhibition of NOS is a characteristic property of the indazole nucleus. Nitration of the indazole ring at positions 5, 6 and 7 results in a graded increase in inhibitory potency. Indazole‐based inhibitors of NOS may prove useful tools with which to evaluate the biological roles of nitric oxide in the central nervous system.
British Journal of Pharmacology – Wiley
Published: Sep 1, 1993
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