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Bioorg Med Chem. 2018 Jul 23;26(12):3588-3595. doi: 10.1016/j.bmc.2018.05.033. Epub 2018 May 23.

Pyrroloquinoline scaffold-based 5-HT6R ligands: Synthesis, quantum chemical and molecular dynamic studies, and influence of nitrogen atom position in the scaffold on affinity.

Author information

1
Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland.
2
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Str., 31-343 Kraków, Poland.
3
Faculty of Chemical Engineering and Technology, Cracow University of Technology, 24 Warszawska Str., 31-155 Kraków, Poland.
4
Research & Development Centre, Celon Pharma S.A., 41A Mokra Str., Kiełpin, 05-092 Łomianki, Poland.
5
Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland. Electronic address: pawel.zajdel@uj.edu.pl.

Abstract

Based on pyrroloquinoline scaffold bearing 5-HT2C agonists, a series of arylsulfonamide derivatives of 1H-pyrrolo[2,3-f]quinoline and 1H-pyrrolo[3,2-h]quinoline, substituted at position 3 with tetrahydropyridine, were synthesized and evaluated in vitro for their affinity for 5-HT6 receptors. A structure-activity relationship study showed that the 1H-pyrrolo[3,2-h]quinoline scaffold was more favorable for 5-HT6R binding than the 1H-pyrrolo[2,3-f]quinoline one, suggesting dependence upon the type of condensation of the pyrrole and quinoline rings. As revealed by quantum-chemical calculations and molecular dynamic studies, position of the quinoline nitrogen atom in the planar pyrroloquinoline skeleton might affect the spatial orientation of the arylsulfonyl fragment, as a result of structure stabilization by internal hydrogen bonds.

KEYWORDS:

1H-Pyrrolo[2,3-f]quinoline; 1H-Pyrrolo[3,2-h]quinoline; 5-HT(6) receptor; Arylsulfonyl-pyrroloquinoline derivatives; Halogen bonding; Hydrogen bonding; Molecular dynamic; Quantum chemical calculations

PMID:
29853337
DOI:
10.1016/j.bmc.2018.05.033
[Indexed for MEDLINE]

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