Laboratory of Medicinal Chemistry, School of Pharmacy , Kitasato University , 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641 , Japan.
Medicinal Research Laboratories, School of Pharmacy , Kitasato University , 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641 , Japan.
ACS Chem Neurosci. 2019 Sep 18;10(9):3939-3945. doi: 10.1021/acschemneuro.9b00368. Epub 2019 Aug 15.
Our previous results showed that naltrindole (NTI) derivatives with certain types of electron-withdrawing groups as an N-substituent showed δ opioid receptor (DOR) inverse agonistic activities. We therefore synthesized N-acylated NTI derivatives - and observed that -benzoyl and -cyclopropanecarbonyl derivatives SYK-736 () and SYK-623 () were DOR full inverse agonists and the -acryloyl derivative was a DOR partial inverse agonist. SKY-623 was over 110-fold more potent than the reference compound ICI-174,864. Both naltriben (NTB) and 7-benzylidenenaltrexone (BNTX) derivatives with -benzoyl and -cyclopropanecarbonyl groups were also DOR full inverse agonists. These -acylated inverse agonists are interesting compounds because they have no basic nitrogen atom, which has been demonstrated to be an important pharmacophore. NTI and BNTX-type DOR inverse agonists SYK-623 and SYK-723 () showed dose-dependent antitussive effects in a mouse cough model induced by citric acid exposure. The antitussive effects by SYK-623 and SYK-723 were significantly attenuated by pretreatment with DOR agonist SNC80.
我们之前的研究结果表明，作为 N-取代基的具有某些类型吸电子基团的纳曲吲哚（NTI）衍生物表现出 δ 阿片受体（DOR）反向激动活性。因此，我们合成了 N-酰化的 NTI 衍生物，并观察到 -苯甲酰基和 -环丙甲酰基衍生物 SYK-736（）和 SYK-623（）是 DOR 完全反向激动剂，-丙烯酰基衍生物是 DOR 部分反向激动剂。SKY-623 的效力比参比化合物 ICI-174,864 高 110 倍以上。具有 -苯甲酰基和 -环丙甲酰基的纳曲布（NTB）和 7-亚苄基纳曲酮（BNTX）衍生物也是 DOR 完全反向激动剂。这些 -酰化的反向激动剂是有趣的化合物，因为它们没有碱性氮原子，该原子已被证明是一个重要的药效团。NTI 和 BNTX 型 DOR 反向激动剂 SYK-623 和 SYK-723（）在柠檬酸暴露诱导的小鼠咳嗽模型中表现出剂量依赖性的镇咳作用。DOR 激动剂 SNC80 预处理显著减弱了 SYK-623 和 SYK-723 的镇咳作用。
