...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of Medicinal Chemistry >Synthesis and Pharmacological Evaluation of 1-Phenyl-3-Thiophenylurea Derivatives as Cannabinoid Type-1 Receptor Allosteric Modulators
【24h】

Synthesis and Pharmacological Evaluation of 1-Phenyl-3-Thiophenylurea Derivatives as Cannabinoid Type-1 Receptor Allosteric Modulators

机译：1-苯基-3-噻吩脲衍生物作为大麻素-1受体颠振调制剂的合成与药理评价

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

We previously reported diarylurea derivatives as cannabinoid type-1 receptor (CB,) allosteric modulators, which were effective in attenuating cocaine-seeking behavior. Herein, we extended the structure-activity relationships of PSNCBAM-1 (2) at the central phenyl ring directly connected to the urea moiety. Replacement with a thiophene ring led to 11 with improved or comparable potencies in calcium mobilization, [S-35]GTP gamma S binding, and cAMP assays, whereas substitution with nonaromatic rings led to significant attenuation of the modulatory activity. These compounds had no inverse agonism in [S-35]GTP gamma S binding, a characteristic that is often thought to contribute to adverse psychiatric effects. While 11 had good metabolic stability in rat liver microsomes, it showed modest solubility and blood-brain barrier permeability. Compound 11 showed an insignificant attenuation of cocaine seeking behavior in rats, most likely due to its limited CNS penetration, suggesting that pharmacokinetics and distribution play a role in translating the in vitro efficacy to in vivo behavior.
机译：我们之前报道了二芳基蛋白衍生物作为大麻素型-1受体（CB，）渐变调节剂，其有效地衰减寻求可卡因的行为。在此，我们将PSNCBAM-1（2）的结构 - 活性关系延伸到直接连接到尿素部分的中央苯环处。替代噻吩环LED为11，在钙动员中具有改进或相当的效力，[S-35]GTPγ的粘合和CAMP测定，而使用非芳环的取代导致调节活性的显着衰减。这些化合物在[S-35]GTPγ的结合中没有反向激动，通常认为有助于不良精神效应的特征。虽然11对大鼠肝微粒体具有良好的代谢稳定性，但它显示出适度的溶解度和血脑屏障渗透性。化合物11表现出对大鼠的可卡因寻求行为的关注衰减，最有可能是由于其有限的CNS渗透率，表明药代动力学和分配在转化体外效率的体内行为中起作用。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号