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首页> 外文期刊>Journal of Medicinal Chemistry >Meta-Substituted Aryl(thio)ethers as Potent Partial Agonists (or Antagonists) for the Histamine H_3 Receptor Lacking a Nitrogen Atom in the Side Chain
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Meta-Substituted Aryl(thio)ethers as Potent Partial Agonists (or Antagonists) for the Histamine H_3 Receptor Lacking a Nitrogen Atom in the Side Chain

机译：间取代的芳基（硫代）醚作为组胺H_3受体在侧链中缺乏氮原子的有效部分激动剂（或拮抗剂）

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摘要

4-(3-Aryloxypropyl)-1H-imidazoles, which possess a meta-positioned substituent in the aryl ring, have been synthesized and tested for activity at histamine H3 receptors. The compounds having a CN, Me, or Br substituent were found to be antagonists, whereas CF_3, Et, i-Pr, t-Bu, COCH_3, or NO_2 substituents remarkably afforded partial agonists when tested in vitro on rat cerebral cortex synaptosomes for inhibition of [~3H]histamine release. The compounds were also active in vivo, and furthermore, the CF3-substituted compound trifluproxim (UCL 1470, 7) acted as a potent full agonist in vivo, having ED_(50) = 0.6 ± 0.3 mg/kg per os in mice for inhibition of brain N-methylhistamine formation. Related structures have also been investigated; homologues 4-[4-(3-(trifluoromethyl)phenoxy)butyl]-1H-imidazole and 4-[2-(3-(trifluoromethyl)phenylthio)ethyl]-1H-imidazole are shown to be partial agonists, whereas the O isostere 4-[2-(3-(trifluoromethyl)phenoxy)ethyl]-1H-imidazole is an antagonist as is the S homologue 4-[3-(3-(trifluoromethyl)phenylthio)propyl]-1H-imidazole and its CH_2 isostere 4-[4-(3-(trifluoromethyl)phenyl)butyl]-1H-imidazole.
机译：已经合成了4-（3-芳氧基丙基）-1H-咪唑，其在芳环中具有间位取代基，并测试了其对组胺H3受体的活性。发现具有CN，Me或Br取代基的化合物是拮抗剂，而当在大鼠大脑皮质突触体上进行体外测试时，CF_3，Et，i-Pr，t-Bu，COCH_3或NO_2取代基可显着提供部分激动剂。 [〜3H]组胺释放量这些化合物还具有体内活性，此外，CF3取代的化合物trifluproxim（UCL 1470，7）在体内具有强大的全效激动剂作用，对小鼠的ED_（50）= 0.6±0.3 mg / kg / os产生抑制作用N-甲基组胺形成的过程。相关结构也已被研究。同源物4- [4-（3-（三氟甲基）苯氧基）丁基] -1H-咪唑和4- [2-（3-（三氟甲基）苯硫基）乙基] -1H-咪唑显示为部分激动剂，而O异构体4- [2-（3-（三（三氟甲基）苯氧基）乙基] -1H-咪唑是拮抗剂，S同源物4- [3-（3-（三氟甲基）苯硫基）丙基] -1H-咪唑及其CH_2异构4- [4-（3-（三氟甲基）苯基）丁基] -1H-咪唑。

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