CHARACTERIZATION OF THE NOVEL NITRIC-OXIDE SYNTHASE INHIBITOR 7-NITROINDAZOLE AND RELATED INDAZOLES - ANTINOCICEPTIVE AND CARDIOVASCULAR EFFECTS

1 7-Nitro indazole (7-NI, 10-50 mg kg-1), 6-nitro indazole and indazol e (25-100 mg kg-1) administered i.p. in the mouse produce dose-related antinociception in the late phase of the formalin-induced hindpaw lic king and acetic acid-induced abdominal constriction assays. The ED50 v alues (mg kg-1) were as follows: 7-NI (27.5 and 22.5), 6-nitro indazol e (62.5 and 44.0) and indazole (41.0 and 48.5) in the two assays respe ctively. 3-Indazolinone, 6 amino indazole and 6-sulphanilimido indazol e (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 indaz ole derivates examined caused overt behavioural changes. 2 The antinoc iceptive effect of 7-NI (25 mg kg-1, i.p.) in the late phase of the fo rmalin-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.). 3 The time course of 7-NI induced antinociception in the mouse was correlated with inhibition of brain (cerebellum) nitric oxid e synthase (NOS) activity. Maximum antinociceptive activity and NOS in hibition were detected 18 - 30 min following i.p. administration. In c ontrast, no antinociceptive effect or inhibition of cerebellar NOS was detected 75 min post-injection. 4 7-NI, 6-nitro indazole, indazole, 3 -indazolinone and 6-amino indazole (all 50 mg kg-1) failed to influenc e mean arterial pressure (MAP) over the 45 min after i.p. administrati on in the anaesthetized mouse. Similarly, 7-NI (25 mg kg-1) administer ed i.v. in the anaesthetized rat did not increase MAP or influence the vasodepressor effect of i.v. injected acetylcholine (ACh) over the sa me period. 5 7-NI (100 mum) did not influence the vasorelaxant effect of ACh (IC50, 0.2 +/- 0.04 muM, cf. 0. 16 0.06 mum, n = 6) in phenylep hrine-precontracted rabbit aortic rings. 6 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 assoc iated with inhibition of in vivo vascular endothelial cells NOS. Accor dingly, 7-NI (or a derivative thereof) may provide an alternative appr oach to the development of novel antinociceptive drugs.