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

作者: P.K. Moore , P. Wallace , Z. Gaffen , S.L. Hart , R.C. Babbedge

DOI: 10.1111/J.1476-5381.1993.TB13795.X

关键词:

摘要: 1. 7-Nitro indazole (7-NI, 10-50 mg kg-1), 6-nitro and (25-100 kg-1) administered i.p. in the mouse produce dose-related antinociception late phase of formalin-induced hindpaw licking acetic acid-induced abdominal constriction assays. The ED50 values (mg were as follows: 7-NI (27.5 22.5), (62.5 44.0) (41.0 48.5) two assays respectively. 3-Indazolinone, 6 amino 6-sulphanilimido (all 50 without effect. With exception 5-nitro (50 which produced sedation, none other derivates examined caused overt behavioural changes. 2. antinociceptive effect (25 kg-1, i.p.) assay was partially (46.7 +/- 16.2%, n = 18) reversed by pretreatment with L- but not D-arginine (both i.p.). 3. time course induced correlated inhibition brain (cerebellum) nitric oxide synthase (NOS) activity. Maximum activity NOS detected 18-30 min following administration. In contrast, no or cerebellar 75 post-injection. 4. 7-NI, indazole, 3-indazolinone 6-amino failed to influence mean arterial pressure (MAP) over 45 after administration anaesthetized mouse. Similarly, i.v. rat did increase MAP vasodepressor injected acetylcholine (ACh) same period.5. (100 microM) vasorelaxant ACh (IC50, 0.2 0.04 microM, cf. 0.16+/-0.06 6) phenylephrine-precontracted rabbit aortic rings.6. These data provide further evidence that results from central is associated vivo vascular endothelial cells NOS. Accordingly, (or a derivative thereof) may an alternative approach development novel drugs.

参考文章(39)
Mary A. Dwyer, David S. Bredt, Solomon H. Snyder, Nitric oxide synthase: Irreversible inhibition by L-NG-Nitroarginine in brain in vitro and in vivo Biochemical and Biophysical Research Communications. ,vol. 176, pp. 1136- 1141 ,(1991) , 10.1016/0006-291X(91)90403-T
Ben Avi Weissman, Tamar Kadar, Rachel Brandeis, Shlomo Shapira, NG-nitro-L-arginine enhances neuronal death following transient forebrain ischemia in gerbils. Neuroscience Letters. ,vol. 146, pp. 139- 142 ,(1992) , 10.1016/0304-3940(92)90062-C
A. Lewis Farr, Oliver H. Lowry, Rose J. Randall, Nira J. Rosebrough, Protein Measurement with the Folin Phenol Reagent Journal of Biological Chemistry. ,vol. 193, pp. 265- 275 ,(1951)
R M Palmer, S Moncada, E A Higgs, NITRIC OXIDE: PHYSIOLOGY, PATHOPHYSIOLOGY, AND PHARMACOLOGY Pharmacological Reviews. ,vol. 43, pp. 109- 142 ,(1991)
S. T. Meller, G. F. Gebhart, Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain. ,vol. 52, pp. 127- 136 ,(1993) , 10.1016/0304-3959(93)90124-8
R. Lisciani, P.Scorza Barcellona, B. Silvestrini, Researches on the topical activity of benzydamine European Journal of Pharmacology. ,vol. 3, pp. 157- 162 ,(1968) , 10.1016/0014-2999(68)90069-1
R.C. Babbedge, P.A. Bland-Ward, S.L. Hart, P.K. Moore, Inhibition of rat cerebellar nitric oxide synthase by 7-nitro indazole and related substituted indazoles British Journal of Pharmacology. ,vol. 110, pp. 225- 228 ,(1993) , 10.1111/J.1476-5381.1993.TB13796.X
P.K. Moore, A.O. Oluyomi, R.C. Babbedge, P. Wallace, S.L. Hart, L-NG-nitro arginine methyl ester exhibits antinociceptive activity in the mouse. British Journal of Pharmacology. ,vol. 102, pp. 198- 202 ,(1991) , 10.1111/J.1476-5381.1991.TB12153.X