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.