Synthesis and structural investigation of some pyrimido[5,4-c]quinolin-4(3H)-one derivatives with a long-chain arylpiperazine moiety as potent 5-HT(1A/2A) and 5-HT(7) receptor ligands |
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Authors: | Lewgowd Wieslawa Bojarski Andrzej J Szczesio Malgorzata Olczak Andrzej Glowka Marek L Mordalski Stefan Stanczak Andrzej |
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Affiliation: | a Department of Hospital Pharmacy, Faculty of Pharmacy, Medical University of Lodz, 1 Muszynski Street, 91-151Lodz, Poland b Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland c Institute of General and Ecological Chemistry, Technical University of Lodz, 116 Zeromski Street, 90-924 Lodz, Poland |
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Abstract: | A series of new pyrimido[5,4-c]quinolin-4(3H)-ones with variable length of the spacer between amide and 4-arylpiperazine moiety were prepared to further explore the role of a terminal portion in the serotonergic activity. The majority of compounds demonstrated high in vitro affinity for 5-HT1A receptor, and moderate-to-low affinity for 5-HT2A and 5-HT7 receptors. X-ray analysis, two-dimensional NMR, conformational studies and docking into the 5-HT1A receptor model were conducted to investigate conformational preferences of selected 5-HT1A receptor ligands in different environments. The extended conformation of tetramethylene derivatives was found in a solid state, in DMSO (for a protonated form) and as a global energy minimum during conformational analysis in simulated water environment. Ligand geometry in top-scored complexes, obtained by docking to a set of 100 receptor models, were either fully extended or with central spacer torsion in synclinal conformation. |
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Keywords: | Pyrimidoquinolones Long-chain arylpiperazines 5-HT receptor ligands Molecular modeling |
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