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

Hidefumi Yoshinaga; Shuji Masumoto; Koji Koyama; Naoya Kinomura; Yuji Matsumoto; Taro Kato; Satoko Baba; Kenji Matsumoto; Tomoko Horisawa; Hitomi Oki; Kazuki Yabuuchi; Toru Kodo

doi:10.1016/j.bmc.2016.10.034

Discovery of SMP-304, a novel benzylpiperidine derivative with serotonin transporter inhibitory activity and 5-HT_1A weak partial agonistic activity showing the antidepressant-like effect

Bioorg Med Chem. 2017 Jan 1;25(1):293-304. doi: 10.1016/j.bmc.2016.10.034. Epub 2016 Oct 29.

Authors

Affiliations

¹ Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan. Electronic address: hidefumi-yoshinaga@ds-pharma.co.jp.
² Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.

PMID: 27865645
DOI: 10.1016/j.bmc.2016.10.034

Abstract

We report the discovery of a novel benzylpiperidine derivative with serotonin transporter (SERT) inhibitory activity and 5-HT_1A 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-HT_1A binding activity, were optimized, leading to compound 35 with potent and balanced dual SERT and 5-HT_1A 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-HT_1A weak partial agonistic activity, which could work as a 5-HT_1A antagonist, displayed faster onset of antidepressant-like effect than a representative SSRI paroxetine in an animal model.

Keywords: 5-HT(1A) receptor; Antidepressant; Benzylpiperidine; Fast onset; Serotonin transporter.

MeSH terms

Animals
Antidepressive Agents / administration & dosage
Antidepressive Agents / chemical synthesis
Antidepressive Agents / pharmacokinetics
Antidepressive Agents / pharmacology*
Cytochrome P-450 CYP2D6 Inhibitors / administration & dosage
Cytochrome P-450 CYP2D6 Inhibitors / chemical synthesis
Cytochrome P-450 CYP2D6 Inhibitors / pharmacokinetics
Cytochrome P-450 CYP2D6 Inhibitors / pharmacology
Dioxanes / administration & dosage
Dioxanes / chemical synthesis
Dioxanes / pharmacokinetics
Dioxanes / pharmacology*
Drug Partial Agonism
Humans
Male
Piperidines / administration & dosage
Piperidines / chemical synthesis
Piperidines / pharmacokinetics
Piperidines / pharmacology*
Rats, Wistar
Selective Serotonin Reuptake Inhibitors / administration & dosage
Selective Serotonin Reuptake Inhibitors / chemical synthesis
Selective Serotonin Reuptake Inhibitors / pharmacokinetics
Selective Serotonin Reuptake Inhibitors / pharmacology*
Serotonin 5-HT1 Receptor Agonists / administration & dosage
Serotonin 5-HT1 Receptor Agonists / chemical synthesis
Serotonin 5-HT1 Receptor Agonists / pharmacokinetics
Serotonin 5-HT1 Receptor Agonists / pharmacology*
Serotonin Plasma Membrane Transport Proteins / metabolism*

Substances

Antidepressive Agents
Cytochrome P-450 CYP2D6 Inhibitors
Dioxanes
Piperidines
SMP-304
Serotonin 5-HT1 Receptor Agonists
Serotonin Plasma Membrane Transport Proteins
Serotonin Uptake Inhibitors
Slc6a4 protein, rat