Antagonists of Serotonin 5-HT6 Receptors. VI. Substituted 3-(Phenylsulfonyl)Quinolines, Synthesis and Structure–Activity Relationships

In continuation of research and development of new high-efficacy drugs based on 5-HT6 receptor antagonists for the treatment of CNS disorders, we synthesized a series of new 3-(phenylsulfonyl)quinoline derivatives, performed their molecular docking, and studied the receptor activity spectrum. It was found that the antagonist activity of the 3-(phenylsulfonyl)quinolines with respect to 5-HT6 receptors depended on the nature of the 4and 8-substituents of the heterocycle. It was expedient for high activity of this type to introduce a tertiary nitrogen atom (dimethylamine or piperazine fragment) in the 8-position and a secondary nitrogen (methylamine fragment) or hydrogen in the 4-position. The most promising compounds were N,N-dimethyl-3-(phenylsulfonyl)quinoline-8-amine (IV, K i f = 0.4 nM), 4-methylamino-8-dimethylamino-3-(phenylsulfonyl)quinoline (XXII, K i f = 0.3 nM), and N-methyl-8-(piperazin-1-yl)-3-(phenylsulfonyl)quinoline-4-amine (XXIII, K i f = 0.9 nM). Antagonist IV exhibited the maximum selectivity; XXIII, the maximum multimodality.