Pharmacological activity of VUF 9153, an isothiourea histamine H3 receptor antagonist.
Pharmacological activity of VUF 9153, an isothiourea histamine H3 receptor antagonist.
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VUF 9153（一种异硫脲组胺 H3 受体拮抗剂）的药理活性。
DOI：
10.1016/0014-2999(93)90632-r
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发表时间：
1993
影响因子：
5
通讯作者：
Celestine T. O'Shaughnessy
中科院分区：
文献类型：
--
作者：
Julie C. Barnes;Jason D. Brown;Nicholas P. Clarke;Jane Clapham;Deborah J. Evans;Celestine T. O'Shaughnessy
组胺 H 3 受体拮抗剂 VUF 9153（S-[3-(4 (5)-咪唑基)] 丙基-N-(4-氯苄基)异硫脲）的药理活性已在体外和体内进行了研究。 VUF 9153 取代与大鼠皮质/海马膜结合的 [3 H] N α-甲基组胺 (pK i= 9.77±0.03)，并拮抗豚鼠回肠离体纵向平滑肌制剂中 (R)-α-甲基组胺对电场刺激的抑制反应 (pK B= 9.95±0.07)。在这些测定中，VUF 9153 的效力比原型 H 3 受体拮抗剂硫过酰胺强 10-50 倍。 VUF 9153 在组胺 H 1 或 H 2 受体的体外功能测定中没有显示出活性或活性非常弱。全身给药 VUF 9153（皮下或口服）剂量依赖性地抑制 [3 H]N α-甲基组胺与大鼠皮质/海马膜的离体结合以及 (R)-α-甲基组胺诱导的诱发反应。在使用的 1 小时预处理时间计算 ED 50 值表明，皮下或口服施用的 VUF 9153 比硫哌丁胺弱约 2 倍。这些数据表明，与硫哌丁胺一样，VUF 9153 在体外是组胺 H 3 受体的有效和选择性拮抗剂，具有穿透血脑屏障接触中枢 H 3 受体的能力，并且可以在体内抑制 H 3 受体介导的功能反应。
The pharmacological activity of the histamine H 3 receptor antagonist VUF 9153 (S-[3-(4 (5)-imidazolyl)] propyl-N-(4-chlorobenzyl) isothiourea) has been investigated in vitro and in vivo. VUF 9153 displaced [3 H] N α-methylhistamine binding to rat cortex/hippocampal membranes (pK i= 9.77±0.03) and antagonised the inhibitory responses to (R)-α-methylhistamine against electrical field stimulation in the isolated longitudinal smooth muscle preparation of guinea-pig ileum (pK B= 9.95±0.07). In these assays, VUF 9153 was 10–50-fold more potent than the prototype H 3 receptor antagonist thioperamide. VUF 9153 showed no or very weak activity in in vitro functional assays for histamine H 1 or H 2 receptors. Systemic administration of VUF 9153 (sc or po) dose-dependently inhibited the ex vivo binding of [3 H] N α-methylhistamine to rat cortex/hippocampal membranes and dipsogenic responses induced by (R)-α-methylhistamine. Calculation of ED 50 values, at the 1 h pretreatment time used, revealed that VUF 9153 administered sc or po, was approximately 2-fold weaker than thioperamide. These data indicate that, like thioperamide, VUF 9153 is a potent and selective antagonist for histamine H 3 receptors in vitro, possesses the ability to penetrate the blood-brain barrier to access central H 3 receptors and can inhibit H 3 receptor-mediated functional responses in vivo.