Anti-inflammatory and anti-allergic activities of hydroxylamine and related compounds
Anti-inflammatory and anti-allergic activities of hydroxylamine and related compounds
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DOI：
10.1248/bpb.25.1436
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发表时间：
2002-11-01
影响因子：
2
通讯作者：
Ito, Y
中科院分区：
文献类型：
--
作者：
Kataoka, H;Horiyama, S;Ito, Y
基于角叉菜胶诱导的大鼠足垫肿胀实验和组胺诱导的大鼠血管渗透性实验，报道了我们合成的几种新型肟和O-酰基肟的抗炎活性。还报道了4 ′-哌啶基苯乙酮和4 ′-吗啉基苯乙酮肟及其O-酰基衍生物的环氧合酶（考克斯）-1抑制作用。为了进一步寻找更有效的非甾体抗炎或抗过敏药物，以肟为原料，与氰基硼氢化钠反应合成了1-羟基氨基-1-（4 ′-哌啶基苯基）乙烷（P-HA）和1-羟基氨基-1-（4 ′-吗啉基苯基）乙烷（M-HA），再与乙酰氯反应合成了NO-二乙酰羟胺（P-HA-Ac和M-HA-Ac）。这些羟胺和NO-二乙酰羟胺明显表现出抑制作用角叉菜胶诱导的小鼠足垫肿胀引起的口服给药（150，37.5毫克/公斤）。经口给药P-HA-Ac（150 mg/kg）可显著抑制小鼠对卵白蛋白的过敏反应。P-HA和M-HA分别以0.5和0.1 mg/耳的剂量经皮给药显著抑制2，4-二硝基氟苯（DNFB）诱导的小鼠接触性超敏反应（IV型）。所有测试的羟胺和NO-二乙酰羟胺均明显抑制考克斯-1和考克斯-2酶活性，对COX-1和考克斯-2的IC 50值分别为1.9-28.7和1.6-2.9 μ M。羟胺（P-HA和M-HA）也显示出5-脂氧合酶抑制作用。
The anti-inflammatory activities of several novel oximes and O-acyl oximes that we synthesized have been reported based on carrageenan-induced rat foot-pad swelling assay and histamine-induced rat vascular permeability assay. A cyclooxygenase (COX)-1 inhibitory effect has also been reported for 4'-piperidinoacetophenone and 4'-morpholinoacetophenone oximes and their O-acyl derivatives. To further search for more effective nonsteroidal anti-inflammatory or anti-allergic drugs, 1-hydroxylamino-1-(4'-piperidinophenyl) ethane (P-HA) and 1-hydroxylamino-1-(4'-morpholinophenyl) ethane (M-HA) were synthesized from the corresponding oximes with sodium cyanoborohydride, and NO-diacetyl hydroxylamines (P-HA-Ac and M-HA-Ac) were prepared from these hydroxylamines using acetyl chloride. These hydroxylamines and NO-diacetyl hydroxylamines clearly exhibited inhibitory effects on mouse carrageenan-induced foot-pad swelling induced by oral administration (150, 37.5 mg/kg). An oral dose of P-HA-Ac (150 mg/kg) significantly inhibited the mouse anaphylactic reaction to ovalbumin measured by the abdominal wall (AW) method. Percutaneous administration of P-HA and M-HA significantly inhibited 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity reaction (type IV) in mice at a dose of 0.5 and 0.1 mg/ear, respectively. All tested hydroxylamines and NO-diacetyl hydroxylamines clearly inhibited both COX-1 and COX-2 enzyme activities with IC50 values of 1.9-28.7 and 1.6-2.9 muM against COX-I and COX-2, respectively. Hydroxylamines (P-HA and M-HA) also showed a 5-lipoxygenase inhibitory effect.