Krause-Heuer Anwen M, Fraser-Spears Rheaclare, Dobrowolski Jeremy C, Ashford Mark E, Wyatt Naomi A, Roberts Maxine P, Gould Georgianna G, Cheah Wai-Ching, Ng Clarissa K L, Bhadbhade Mohan, Zhang Bo, Greguric Ivan, Wheate Nial J, Kumar Naresh, Koek Wouter, Callaghan Paul D, Daws Lynette C, Fraser Benjamin H
The Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC NSW 2232, Australia.
Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Eur J Med Chem. 2017 Sep 8;137:476-487. doi: 10.1016/j.ejmech.2017.06.011. Epub 2017 Jun 7.
Herein we describe the synthesis and evaluation of antidepressant properties of seven analogues (1-7) of the low affinity/high capacity transporter blocker decynium-22 (D-22). All analogues (1-7) were synthesized via base promoted coupling reactions between N-alkylated-2-methylquinolinium iodides or N-alkylated-4-methylquinolinium iodides and electrophilic N-alkylated-2-iodoquinolinium iodides. All final compounds were purified by re-crystallization or preparative HPLC and initial evaluation studies included; 1) screening for in vitro α1-adrenoceptor activity (a property that can lead to unwanted side-effects), 2) measuring antidepressant-like activity in a mouse tail suspension test (TST), and 3) measuring effects upon mouse locomotion. The results showed some analogues have lower affinities at α1-adrenoceptors compared to D-22 and showed antidepressant-like activity without the need for co-administration of SSRIs. Additionally, many analogues did not affect mouse locomotion to the same extent as D-22. Plans for additional evaluations of these promising analogues, including measurement of antidepressant-like activity with co-administration of selective serotonin re-uptake inhibitors (SSRIs), are outlined.
在此，我们描述了低亲和力/高容量转运体阻滞剂癸鎓-22（D-22）的七种类似物（1-7）的合成及其抗抑郁特性的评估。所有类似物（1-7）均通过N-烷基化-2-甲基喹啉鎓碘化物或N-烷基化-4-甲基喹啉鎓碘化物与亲电N-烷基化-2-碘喹啉鎓碘化物之间的碱促进偶联反应合成。所有最终化合物均通过重结晶或制备型高效液相色谱法纯化，初步评估研究包括：1）体外α1-肾上腺素能受体活性筛选（一种可能导致不良副作用的特性），2）在小鼠悬尾试验（TST）中测量抗抑郁样活性，以及3）测量对小鼠运动的影响。结果表明，与D-22相比，一些类似物对α1-肾上腺素能受体的亲和力较低，并且在无需联合使用选择性5-羟色胺再摄取抑制剂（SSRI）的情况下表现出抗抑郁样活性。此外，许多类似物对小鼠运动的影响程度与D-22不同。文中概述了对这些有前景的类似物进行进一步评估的计划，包括联合使用选择性5-羟色胺再摄取抑制剂（SSRI）测量抗抑郁样活性。
