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.
Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Bioorg Med Chem Lett. 2020 Jun 15;30(12):127176. doi: 10.1016/j.bmcl.2020.127176. Epub 2020 Apr 8.
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.
我们最近报道了 δ 阿片受体（DOR）拮抗剂纳曲吲哚（NTI）中 N-取代基的详细说明，使得 DOR 活性从完全反向激动剂调节为弱部分激动剂。酰胺型 NTI 衍生物的研究表明，N-苯乙酰基和 N-二氢肉桂酰衍生物 3a 和 3b 是 DOR 的完全激动剂。同样的转化应用于 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表现出剂量依赖性抗抑郁样作用。6a 的抗抑郁样作用似乎比在体外试验中更有效的 KNT-127 更强。酰胺型化合物 6a 可能更充分地渗透到中枢神经系统。
