Medicinal Chemistry, NeuroSearch Sweden AB, Biotech Center, Arvid Wallgrens Backe 20, SE-413 46 Gothenburg, Sweden.
Eur J Med Chem. 2013 May;63:578-88. doi: 10.1016/j.ejmech.2013.03.006. Epub 2013 Mar 14.
To further investigate the structure-activity relationship (SAR) of the 5-hydroxytryptamine type 6 (5-HT6) receptor agonist 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (EMD386088, 6), a series of 2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles were synthesized, and in vitro affinity to, and functional activity at 5-HT6 receptors was tested. We focused on substituents made at the indole N(1)-, 2- and 5-positions and these were found to not only influence the affinity at 5-HT6 receptors but also the intrinsic activity leading to antagonists, partial agonists and full agonists. In order for a compound to demonstrate potent 5-HT6 receptor agonist properties, the indole N(1) should be unsubstituted, an alkyl group such as 2-methyl is needed and finally halogen substituents in the indole 5-position (fluoro, chloro or, bromo) were essential requirements. However, the introduction of a benzenesulfonyl group at N(1)-position switched the full agonist 6 to be a 5-HT6 receptor antagonist (30). A few compounds within the 2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles were also screened for off-targets and generally they displayed low affinity for other 5-HT subtypes and serotonin transporter protein (SERT).
为了进一步研究 5-羟色胺 6 型（5-HT6）受体激动剂 5-氯-2-甲基-3-（1,2,3,6-四氢吡啶-4-基）-1H-吲哚（EMD386088，6）的构效关系（SAR），合成了一系列 2-甲基-3-（1,2,3,6-四氢吡啶-4-基）-1H-吲哚，并测试了它们对 5-HT6 受体的体外亲和力和功能活性。我们专注于吲哚 N(1)-、2-和 5-位的取代基，这些取代基不仅影响 5-HT6 受体的亲和力，还影响内在活性，导致拮抗剂、部分激动剂和完全激动剂。为了使化合物表现出有效的 5-HT6 受体激动剂特性，吲哚 N(1)应未取代，需要烷基如 2-甲基，并且吲哚 5-位的卤素取代基（氟、氯或溴）是必需的。然而，在 N(1)-位引入苯磺酰基将完全激动剂 6 转变为 5-HT6 受体拮抗剂（30）。2-甲基-3-（1,2,3,6-四氢吡啶-4-基）-1H-吲哚中的一些化合物也被筛选为非靶点，它们通常对其他 5-HT 亚型和 5-羟色胺转运蛋白（SERT）显示出低亲和力。
