Alhaider A A, Abdelkader M A, Lien E J
J Med Chem. 1985 Oct;28(10):1394-8. doi: 10.1021/jm00148a004.
This work represents the design, synthesis, and pharmacological testing of 4-phenylquinoline derivatives as potential antidepressants. Various modifications of substituents at the 2-position of the quinoline ring were tried, and two main series of derivatives were synthesized. In the first series, an open (dialkylamino)alkyl chain is linked to the 2-position of the quinoline ring by isosteres. The second approach involved the synthesis of a novel analogue of trazodone with a 4-phenylquinoline grouping replacing the chlorophenyl group of trazodone. The potential antidepressant activity of these new compounds has been demonstrated by their antagonism to the reserpine-induced hypothermia in mice. Both length of the side chain and isosteric displacements within the side chain affect the value of the ED50 obtained. Compounds having three atoms separating the terminal nitrogen from the quinoline ring were found to be more active than those with four atoms. The 2-thia derivatives were devoid of antidepressant activity. Replacement of the open side chain at the 2-position of the quinoline ring by piperazine or substituted piperazines resulted in new compounds that are slightly more potent than imipramine.
这项工作展示了4-苯基喹啉衍生物作为潜在抗抑郁药的设计、合成及药理测试。尝试了喹啉环2-位取代基的各种修饰，并合成了两个主要系列的衍生物。在第一个系列中，一个开链（二烷基氨基）烷基链通过电子等排体连接到喹啉环的2-位。第二种方法涉及合成一种新型曲唑酮类似物，其中4-苯基喹啉基团取代了曲唑酮的氯苯基。这些新化合物的潜在抗抑郁活性已通过它们对小鼠利血平诱导的体温过低的拮抗作用得到证明。侧链长度和侧链内的电子等排取代都影响所获得的半数有效剂量（ED50）值。发现末端氮与喹啉环之间间隔三个原子的化合物比间隔四个原子的化合物更具活性。2-硫杂衍生物没有抗抑郁活性。用哌嗪或取代哌嗪取代喹啉环2-位的开链侧链，得到了比丙咪嗪稍强效的新化合物。
