Abstract
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.
Keywords:
5-HT(1A) receptor; Antidepressant; Benzylpiperidine; Fast onset; Serotonin transporter.
Copyright © 2016 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Antidepressive Agents / administration & dosage
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Antidepressive Agents / chemical synthesis
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Antidepressive Agents / pharmacokinetics
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Antidepressive Agents / pharmacology*
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Cytochrome P-450 CYP2D6 Inhibitors / administration & dosage
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Cytochrome P-450 CYP2D6 Inhibitors / chemical synthesis
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Cytochrome P-450 CYP2D6 Inhibitors / pharmacokinetics
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Cytochrome P-450 CYP2D6 Inhibitors / pharmacology
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Dioxanes / administration & dosage
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Dioxanes / chemical synthesis
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Dioxanes / pharmacokinetics
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Dioxanes / pharmacology*
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Drug Partial Agonism
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Humans
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Male
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Piperidines / administration & dosage
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Piperidines / chemical synthesis
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Piperidines / pharmacokinetics
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Piperidines / pharmacology*
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Rats, Wistar
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Selective Serotonin Reuptake Inhibitors / administration & dosage
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Selective Serotonin Reuptake Inhibitors / chemical synthesis
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Selective Serotonin Reuptake Inhibitors / pharmacokinetics
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Selective Serotonin Reuptake Inhibitors / pharmacology*
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Serotonin 5-HT1 Receptor Agonists / administration & dosage
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Serotonin 5-HT1 Receptor Agonists / chemical synthesis
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Serotonin 5-HT1 Receptor Agonists / pharmacokinetics
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Serotonin 5-HT1 Receptor Agonists / pharmacology*
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Serotonin Plasma Membrane Transport Proteins / metabolism*
Substances
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Antidepressive Agents
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Cytochrome P-450 CYP2D6 Inhibitors
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Dioxanes
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Piperidines
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SMP-304
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Serotonin 5-HT1 Receptor Agonists
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Serotonin Plasma Membrane Transport Proteins
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Serotonin Uptake Inhibitors
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Slc6a4 protein, rat