title: Discovery of SMP-304, a novel benzylpiperidine derivative with serotonin transporter inhibitory activity and 5-HT1Aweak partial agonistic activity showing the antidepressant-like effect.
abstract: We report the discovery of a novel benzylpiperidine derivative with serotonin transporter (SERT) inhibitory activity and 5-HT1Areceptor 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-HT1Abinding activity, were optimized, leading to compound 35 with potent and balanced dual SERT and 5-HT1Abinding 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-HT1Aweak partial agonistic activity, which could work as a 5-HT1Aantagonist, displayed faster onset of antidepressant-like effect than a representative SSRI paroxetine in an animal model.
authors.affiliation: 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.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Yoshinaga
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Masumoto
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Koyama
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Kinomura
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Kato
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Baba
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Horisawa
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Oki
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yabuuchi
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kodo
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D004146:Dioxanes / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D054333:Drug Partial Agonism; D006801:Humans; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D017208:Rats, Wistar; D058825:Serotonin 5-HT1 Receptor Agonists / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004146:Dioxanes; D010880:Piperidines; D058825:Serotonin 5-HT1 Receptor Agonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C000625533:SMP-304; C493232:Slc6a4 protein, rat
keywords: 5-HT(1A) receptor; Antidepressant; Benzylpiperidine; Fast onset; Serotonin transporter