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Eur J Med Chem. 2017 Jul 28;135:117-124. doi: 10.1016/j.ejmech.2017.04.033. Epub 2017 Apr 13.

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

Author information

1
Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Kraków, Poland. Electronic address: dlazewska@cm-uj.krakow.pl.
2
Department of Medicinal Chemistry Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.
3
Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
4
Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
5
Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Kraków, Poland. Electronic address: j.handzlik@uj.edu.pl.

Abstract

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.

KEYWORDS:

1,3,5-Triazine; 5-HT(6) ligands; CNS drugability; Docking; Serotonin receptors

PMID:
28441580
DOI:
10.1016/j.ejmech.2017.04.033
[Indexed for MEDLINE]

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