Discovery of SMP-304, a novel benzylpiperidine derivative with serotonin transporter inhibitory activity and 5-HT1A weak partial agonistic activity showing the antidepressant-like effect
| Autor: | Hitomi Oki, Satoko Baba, Naoya Kinomura, Tomoko Horisawa, Yuji Matsumoto, Shuji Masumoto, Toru Kodo, Hidefumi Yoshinaga, Kazuki Yabuuchi, Kenji Matsumoto, Koji Koyama, Taro Kato |
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| Rok vydání: | 2017 |
| Předmět: |
Serotonin uptake
biology Chemistry Organic Chemistry Clinical Biochemistry Antagonist Pharmaceutical Science Pharmacology Inhibitory postsynaptic potential Biochemistry Paroxetine 030227 psychiatry 03 medical and health sciences 0302 clinical medicine Drug Discovery Alkoxy group biology.protein medicine Molecular Medicine Antidepressant Molecular Biology 030217 neurology & neurosurgery Serotonin transporter 5-HT receptor medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 25:293-304 |
| ISSN: | 0968-0896 |
| Popis: | We report the discovery of a novel benzylpiperidine derivative with serotonin transporter (SERT) inhibitory activity and 5-HT1A receptor weak partial agonistic activity showing the antidepressant-like effect. The 3-methoxyphenyl group and the phenethyl group of compound 1, which has weak SERT binding activity, but potent 5-HT1A binding activity, were optimized, leading to compound 35 with potent and balanced dual SERT and 5-HT1A binding activity, but also potent CYP2D6 inhibitory activity. Replacement of the methoxy group in the left part of compound 35 with a larger alkoxy group, such as ethoxy, isopropoxy or methoxy-ethoxy group ameliorated CYP2D6 inhibition, giving SMP-304 as a candidate. SMP-304 with serotonin uptake inhibitory activity and 5-HT1A weak partial agonistic activity, which could work as a 5-HT1A antagonist, displayed faster onset of antidepressant-like effect than a representative SSRI paroxetine in an animal model. |
| Databáze: | OpenAIRE |
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