5-HT1A and 5-HT2A receptors affinity, docking studies and pharmacological evaluation of a series of 8-acetyl-7-hydroxy-4-methylcoumarin derivatives.
Bioorg Med Chem
; 26(2): 527-535, 2018 01 15.
Article
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| MEDLINE
| ID: mdl-29269256
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-0.9â¯nM, 6a-0.5â¯nM, 10a-0.6â¯nM, 3b-0.9â¯nM, 6b-1.5â¯nM, 10b-1â¯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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Cumarinas
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Receptor de Serotonina 5-HT1A
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Receptor de Serotonina 5-HT2A
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Antagonistas del Receptor de Serotonina 5-HT1
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Antagonistas del Receptor de Serotonina 5-HT2
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Simulación del Acoplamiento Molecular
Límite:
Animals
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Humans
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Male
Idioma:
En
Año:
2018
Tipo del documento:
Article