5-HT1A and 5-HT2A receptors affinity, docking studies and pharmacological evaluation of a series of 8-acetyl-7-hydroxy-4-methylcoumarin derivatives

Publication date: Available online 9 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Kinga Ostrowska, Dawid Grzeszczuk, Monika Głuch-Lutwin, Anna Gryboś, Agata Siwek, Anna Leśniak, Mariusz Sacharczuk, Bartosz Trzaskowski
In this work we describe the synthesis, docking studies and biological evaluation of a focused library of novel arylpiperazinyl derivatives of 8-acetyl-7-hydroxy-4-methylcoumarin. The new compounds were screened for their 5-HT1A and 5-HT2A receptor affinity. Among the evaluated compounds, six displayed high affinities to 5-HT1A receptors (4a-0.9 nM, 6a-0.5 nM, 10a-0.6 nM, 3b-0.9 nM, 6b-1.5 nM, 10b-1 nM). Compound 6a and 10a bearing a bromo- or methoxy- substituent in ortho position of the piperazine phenyl ring, were identified as potent antagonists of the 5-HT1A receptors. In the tail suspension test, mice injected with 6a showed a dose-dependent increase in depressive-like behavior that was related to a decrease in locomotor activity. Compound 10a did not decrease or prolong immobility time nor did it affect home cage activity. Molecular docking studies using 5-HT1A and 5-HT2A homology models revealed structural basis of the high affinity of ortho-substituted derivatives and subtle changes in amino acid interactions patterns depending on the length of the alkyl linker.

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