5-HT1A and 5-HT2A receptors affinity, docking studies and pharmacological evaluation of a series of 8-acetyl-7-hydroxy-4-methylcoumarin derivatives. Issue 2 (15th January 2018)

• Record Type: Journal Article
• Authors: Ostrowska, Kinga; Grzeszczuk, Dawid; Głuch-Lutwin, Monika; Gryboś, Anna; Siwek, Agata; Leśniak, Anna; Sacharczuk, Mariusz; Trzaskowski, Bartosz
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 2(2018)
• Page Start: 527
• Page End: 535
• Publication Date: 2018-01-15
• Subjects: Coumarin derivatives -- 5-HT1A receptor ligands -- 5-HT2A receptor ligands -- Molecular docking -- CNS activity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.12.016
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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.