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

Abstract The work describes a discovery of new chemical family of potent ligands for the 5-HT 6 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 H 4 receptor but fitted in 3/4 of pharmacophore features of the 5-HT 6 R ligand, occurred to be a moderate 5-HT 6 R 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-HT 6 R. The most active compounds displayed a potent affinity for the 5-HT 6 R 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.