Discovery of DSP-1053, a novel benzylpiperidine derivative with potent serotonin transporter inhibitory activity and partial 5-HT1A receptor agonistic activity.
Bioorg Med Chem
; 26(8): 1614-1627, 2018 05 01.
Article
em En
| MEDLINE
| ID: mdl-29456112
ABSTRACT
We have previously shown that SMP-304, a serotonin uptake inhibitor with weak 5-HT1A partial agonistic activity, may act under high serotonin levels as a 5-HT1A antagonist that improves the onset of paroxetine in the rat swimming test. However, SMP-304 is mostly metabolized by CYP2D6, indicating limited efficacy among individuals and increased side effects. To reduce CYP2D6 metabolic contribution and enhance SERT/5-HT1A binding affinity, we carried out a series of substitutions at the bromine atom in the left part of the benzene ring of SMP-304 and replaced the right part of SMP-304 with a chroman-4-one. This optimization work led to the identification of the antidepressant candidate DSP-1053 as a potent SERT inhibitor with partial 5-HT1A receptor agonistic activity. DSP-1053 showed low CYP2D6 metabolic contribution and a robust increase in serotonin levels in the rat frontal cortex.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperidinas
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Inibidores Seletivos de Recaptação de Serotonina
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Receptor 5-HT1A de Serotonina
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Proteínas da Membrana Plasmática de Transporte de Serotonina
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Agonistas do Receptor 5-HT1 de Serotonina
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Bioorg Med Chem
Ano de publicação:
2018
Tipo de documento:
Article