Synthesis of novel 2-(piperazino-1-yl-alkyl)-1H-benzimidazole derivates and assessment of their interactions with the D2 dopamine receptor

Jelena Z. Penjišević, Deana B. Andrić, Vladimir B. Šukalović, Goran M. Roglić, Vukić Šoškić, Slađana Kostić-Rajačić

Abstract


A total of 14 novel arylpiperazines were synthesized, and pharmacologically
evaluated by measuring their affinities towards the D2 dopamine receptor
(DRD2) in a [3H]spiperone competition assay. All the herein described compounds
consist of a benzimidazole moiety connected to N-(2-methoxyphenyl)piperazine
via linkers of various lengths. Molecular docking analysis and molecular dynamics
simulations were performed on the DRD2–arylpiperazine complexes with the
objective of exploring the receptor–ligand interactions and properties of the receptor
binding site. The recently published crystal structure of DRD2 was used
throughout this study. The major finding is that high affinity arylpiperazines must
interact with both the orthosteric binding site and the extended binding pocket of
DRD2 and therefore should contain a linker of 5 or 6 methylene groups long.


Keywords


arylpiperazines; molecular dynamics; molecular docking; receptor binding site

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DOI: https://doi.org/10.2298/JSC181029104P

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