Characterization of the novel nitric oxide synthase inhibitor 7‐nitro indazole and related indazoles: antinociceptive and cardiovascular effects

Abstract

7‐Nitro indazole (7‐NI, 10–50 mg kg−1), 6‐nitro indazole and indazole (25–100 mg kg−1) administered i.p. in the mouse produce dose‐related antinociception in the late phase of the formalin‐induced hindpaw licking and acetic acid‐induced abdominal constriction assays. The ED 50 values (mg kg−1) were as follows: 7‐NI (27.5 and 22.5), 6‐nitro indazole (62.5 and 44.0) and indazole (41.0 and 48.5) in the two assays respectively. 3‐Indazolinone, 6 amino indazole and 6‐sulphanilimido indazole (all 50 mg kg−1) were without effect. With the exception of 5‐nitro indazole (50 mg kg−1) which produced sedation, none of the other indazole derivates examined caused overt behavioural changes. The antinociceptive effect of 7‐NI (25 mg kg−1, i.p.) in the late phase of the formalin‐induced hindpaw licking assay was partially (46.7 ± 16.2%, n = 18) reversed by pretreatment with l‐ but not d‐arginine (both 50 mg kg−1, i.p.). The time course of 7‐NI induced antinociception in the mouse was correlated with inhibition of brain (cerebellum) nitric oxide synthase (NOS) activity. Maximum antinociceptive activity and NOS inhibition were detected 18–30 min following i.p. administration. In contrast, no antinociceptive effect or inhibition of cerebellar NOS was detected 75 min post‐injection. 7‐NI, 6‐nitro indazole, indazole, 3‐indazolinone and 6‐amino indazole (all 50 mg kg−1) failed to influence mean arterial pressure (MAP) over the 45 min after i.p. administration in the anaesthetized mouse. Similarly, 7‐NI (25 mg kg−1) administered i.v. in the anaesthetized rat did not increase MAP or influence the vasodepressor effect of i.v. injected acetylcholine (ACh) over the same period. 7‐NI (100 μ m) did not influence the vasorelaxant effect of ACh (IC 50, 0.2 ± 0.04 μ m, cf. 0.16 ± 0.06 μ m, n = 6) in phenylephrine‐precontracted rabbit aortic rings. These data provide further evidence that antinociception following administration of 7‐NI in the mouse results from inhibition of central NOS activity and is not associated with inhibition of in vivo vascular endothelial cells NOS. Accordingly, 7‐NI (or a derivative thereof) may provide an alternative approach to the development of novel antinociceptive drugs.