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

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 1; pp. 293 - 304
• Main Authors: Yoshinaga, Hidefumi, Masumoto, Shuji, Koyama, Koji, Kinomura, Naoya, Matsumoto, Yuji, Kato, Taro, Baba, Satoko, Matsumoto, Kenji, Horisawa, Tomoko, Oki, Hitomi, Yabuuchi, Kazuki, Kodo, Toru
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01-01-2017
• Subjects: 5-HT1A receptor; Antidepressant; Benzylpiperidine; Fast onset; Serotonin transporter; Antidepressant; Serotonin transporter; ITSYNQXGEQDUJI-UHFFFAOYSA-N; Benzylpiperidine; 5-HT1A receptor; Fast onset
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.10.034

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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.