The computer-aided discovery of novel family of the 5-HT6 serotonin receptor ligands among derivatives of 4-benzyl-1,3,5-triazine

作者：Lazewska Dorota^*; Kurczab Rafal; Wiecek Malgorzata; Kaminska Katarzyna; Satala Grzegorz; Jastrebska Wiesek Magdalena; Partyka Anna; Bojarski Andrzej J; Wesolowska Anna; Kiec Kononowicz Katarzyna; Handzlik Jadwiga^*

来源：European Journal of Medicinal Chemistry, 2017, 135: 117-124.

DOI：10.1016/j.ejmech.2017.04.033

• Serotonin receptors
• 5-HT6 ligands
• 1,3,5-Triazine
• Docking
• CNS drugability

The work describes a discovery of new chemical family of potent ligands for the 5-HT6 serotonin receptors. During the search for new histamine H-4 receptor antagonists among 1,3,5-triazine derivatives, compound 2 (4-benzyl-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine) was found. Compound 2, weakly active for the H4 receptor but fitted in 3/4 of pharmacophore features of the 5-HT6R ligand, occurred to be a moderate 5-HT6R agent, useful as a lead structure for further modifications. A series of new derivatives (3-19) of the lead 2 was synthesized, evaluated in the radioligand binding assay (RBA) and explored in comprehensive molecular modelling, including both pharmacophore- and structure based approaches with docking to the homology model of 5-HT6R. The most active compounds displayed a potent affinity for the 5-HT6R in the nanomolar range (K-i = 20-30 nM), some of them (4,11 and 19) were tested in the rat forced swim test that revealed their antidepressant-like effect. SAR-analysis on the basis of both, RBA and docking results, indicated that action on the receptor is related to the hydrophobicity and the size of aromatic moiety substituted by a methylene linker at the position 4 of 1,3,5-triazine.

• 出版日期2017-7-28