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


:The work describes a discovery of new chemical family of potent ligands for the 5-HT6 serotonin receptors. During the search for new histamine H4 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 (Ki = 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.


Eur J Med Chem


Łażewska D,Kurczab R,Więcek M,Kamińska K,Satała G,Jastrzębska-Więsek M,Partyka A,Bojarski AJ,Wesołowska A,Kieć-Kononowicz K,Handzlik J




Has Abstract


2017-07-28 00:00:00












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    authors: Mugnaini C,Rabbito A,Brizzi A,Palombi N,Petrosino S,Verde R,Di Marzo V,Ligresti A,Corelli F

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    更新日期:2018-04-25 00:00:00

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    authors: Logé C,Testard A,Thiéry V,Lozach O,Blairvacq M,Robert JM,Meijer L,Besson T

    更新日期:2008-07-01 00:00:00