Abstract
The synthesis and structure-activity relationship of a novel series of compounds with combined effects on 5-HT(3A) and 5-HT(1A) receptors and on the serotonin (5-HT) transporter (SERT) are described. Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT(1A) (K(i) = 15 nM), 5-HT(1B) (K(i) = 33 nM), 5-HT(3A) (K(i) = 3.7 nM), 5-HT(7) (K(i) = 19 nM), and noradrenergic β(1) (K(i) = 46 nM) receptors, and SERT (K(i) = 1.6 nM). Compound 5m displayed antagonistic properties at 5-HT(3A) and 5-HT(7) receptors, partial agonist properties at 5-HT(1B) receptors, agonistic properties at 5-HT(1A) receptors, and potent inhibition of SERT. In conscious rats, 5m significantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5m is a novel multimodal serotonergic compound, and 5m is currently in clinical development for major depressive disorder.
MeSH terms
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Animals
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Antidepressive Agents / chemical synthesis*
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Antidepressive Agents / chemistry
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Antidepressive Agents / pharmacology
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Cell Line
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Depressive Disorder, Major / drug therapy*
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Drug Partial Agonism
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Drug Stability
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Hippocampus / drug effects
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Hippocampus / metabolism
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Humans
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In Vitro Techniques
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Microsomes, Liver / metabolism
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Oocytes / drug effects
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Oocytes / physiology
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology
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Radioligand Assay
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Rats
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Receptor, Serotonin, 5-HT1A / metabolism
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Receptor, Serotonin, 5-HT2C / metabolism
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Receptors, Serotonin / metabolism
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Receptors, Serotonin, 5-HT1 / metabolism
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Receptors, Serotonin, 5-HT3 / metabolism
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Recombinant Proteins / agonists
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Recombinant Proteins / antagonists & inhibitors
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Selective Serotonin Reuptake Inhibitors / chemical synthesis
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Selective Serotonin Reuptake Inhibitors / chemistry
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Selective Serotonin Reuptake Inhibitors / pharmacology
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Serotonin / metabolism
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Serotonin 5-HT1 Receptor Agonists / chemical synthesis
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Serotonin 5-HT1 Receptor Agonists / chemistry
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Serotonin 5-HT1 Receptor Agonists / pharmacology
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Serotonin 5-HT3 Receptor Antagonists / chemical synthesis
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Serotonin 5-HT3 Receptor Antagonists / chemistry
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Serotonin 5-HT3 Receptor Antagonists / pharmacology
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Serotonin Plasma Membrane Transport Proteins / metabolism
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Structure-Activity Relationship
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Sulfides / chemical synthesis*
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Sulfides / chemistry
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Sulfides / pharmacology
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Vortioxetine
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Xenopus
Substances
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Antidepressive Agents
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Piperazines
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Receptor, Serotonin, 5-HT2C
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Receptors, Serotonin
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Receptors, Serotonin, 5-HT1
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Receptors, Serotonin, 5-HT3
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Recombinant Proteins
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Serotonin 5-HT1 Receptor Agonists
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Serotonin 5-HT3 Receptor Antagonists
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Serotonin Plasma Membrane Transport Proteins
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Serotonin Uptake Inhibitors
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Sulfides
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serotonin 7 receptor
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Receptor, Serotonin, 5-HT1A
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Serotonin
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Vortioxetine