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Bioorg Med Chem. 2017 Jul 15;25(14):3638-3648. doi: 10.1016/j.bmc.2017.04.046. Epub 2017 May 4.

The impact of the halogen bonding on D2 and 5-HT1A/5-HT7 receptor activity of azinesulfonamides of 4-[(2-ethyl)piperidinyl-1-yl]phenylpiperazines with antipsychotic and antidepressant properties.

Author information

1
Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland.
2
Institute of Pharmacology, Polish Academy of Sciences, Department of Medicinal Chemistry, 12 Smętna Street, 31-343 Krakow, Poland.
3
Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland.
4
Department of Organic Chemistry, Medical University of Silesia, 4 Jagiellońska Street, 41-200 Sosnowiec, Poland.
5
Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland. Electronic address: pawel.zajdel@uj.edu.pl.

Abstract

A series of azinesulfonamides of long-chain arylpiperazine derivatives with semi-rigid alkylene spacer was designed, synthesized, and biologically evaluated using in vitro methods for their affinity for dopaminergic D2 and serotoninergic 5-HT1A, 5-HT2A, 5-HT6 and 5-HT7 receptors. Docking to homology models revealed a possible halogen bond formation in complexes of the most potent ligands and the target receptors. The study allowed for the identification of compound 5-({4-(2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl)piperidin-1-yl}sulfonyl)quinoline (21), which behaved as D2, 5-HT1A and 5-HT7 receptor antagonist. In preliminary in vivo studies, compound 21 displayed distinct antipsychotic properties in the MK-801-evoked hyperactivity test in mice at a dose of 10mg/kg, and exerted antidepressant-like effect in a forced swim test in mice (MED=0.625mg/kg, i.p.).

KEYWORDS:

Azinesulfonamides; Depression; Halogen bonding; Multi-target ligands; Multimodal dopamine/serotonin ligands; Schizophrenia; Semi-rigid long-chain arylpiperazines

PMID:
28529043
DOI:
10.1016/j.bmc.2017.04.046
[Indexed for MEDLINE]

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