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Discovery of δ opioid receptor full agonists lacking a basic nitrogen atom and their antidepressant-like effects.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-04-08 , DOI: 10.1016/j.bmcl.2020.127176 Hideaki Fujii 1 , Yota Uchida 2 , Marie Shibasaki 2 , Moeno Nishida 3 , Toshinori Yoshioka 3 , Riho Kobayashi 3 , Ayaka Honjo 2 , Kennosuke Itoh 1 , Daisuke Yamada 3 , Shigeto Hirayama 1 , Akiyoshi Saitoh 3
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-04-08 , DOI: 10.1016/j.bmcl.2020.127176 Hideaki Fujii 1 , Yota Uchida 2 , Marie Shibasaki 2 , Moeno Nishida 3 , Toshinori Yoshioka 3 , Riho Kobayashi 3 , Ayaka Honjo 2 , Kennosuke Itoh 1 , Daisuke Yamada 3 , Shigeto Hirayama 1 , Akiyoshi Saitoh 3
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We have recently reported that the elaboration of the N-substituent in the δ opioid receptor (DOR) antagonist naltrindole (NTI) enabled the regulation of the DOR activities from full inverse agonists to weak partial agonists. The investigations of amide-type NTI derivatives revealed that N-phenylacetyl and N-dihydrocinnamoyl derivatives 3a and 3b were DOR full agonists. The same transformations were applied to a DOR agonist KNT-127 to provide the more potent DOR agonists 6a and 6b. Among the tested compounds, the most efficacious compound 6a showed dose-dependent antidepressant-like effects in the mouse forced swim test. The antidepressant-like effects by 6a seemed to be more potent than those of KNT-127, which is a more potent DOR agonist in in vitro assays. The amide-type compound like 6a may more fully penetrate into the central nervous system.
中文翻译：
缺乏碱性氮原子的δ阿片受体完全激动剂的发现及其类似抗抑郁药的作用。
我们最近报道，δ阿片受体（DOR）拮抗剂纳曲酮（NTI）中N取代基的修饰使DOR活性的调节从完全反向激动剂变为弱部分激动剂。酰胺型NTI衍生物的研究表明，N-苯基乙酰基和N-二氢肉桂酰基衍生物3a和3b是DOR完全激动剂。将相同的转化应用于DOR激动剂KNT-127，以提供更有效的DOR激动剂6a和6b。在测试的化合物中，最有效的化合物6a在小鼠强迫游泳试验中显示出剂量依赖性的抗抑郁药样作用。6a的抗抑郁样作用似乎比KNT-127更为有效，后者在体外测定中是更有效的DOR激动剂。像6a这样的酰胺类化合物可能会更充分地渗入中枢神经系统。
更新日期：2020-04-08
中文翻译：
缺乏碱性氮原子的δ阿片受体完全激动剂的发现及其类似抗抑郁药的作用。
我们最近报道，δ阿片受体（DOR）拮抗剂纳曲酮（NTI）中N取代基的修饰使DOR活性的调节从完全反向激动剂变为弱部分激动剂。酰胺型NTI衍生物的研究表明，N-苯基乙酰基和N-二氢肉桂酰基衍生物3a和3b是DOR完全激动剂。将相同的转化应用于DOR激动剂KNT-127，以提供更有效的DOR激动剂6a和6b。在测试的化合物中，最有效的化合物6a在小鼠强迫游泳试验中显示出剂量依赖性的抗抑郁药样作用。6a的抗抑郁样作用似乎比KNT-127更为有效，后者在体外测定中是更有效的DOR激动剂。像6a这样的酰胺类化合物可能会更充分地渗入中枢神经系统。
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