Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder.
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Bang-Andersen B, Ruhland T, Jorgensen M, Smith G, Frederiksen K, Jensen KG, Zhong H, Nielsen SM, Hogg S, Mork A, Stensbol TB
Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder.
J Med Chem. 2011 May 12;54(9):3206-21. doi: 10.1021/jm101459g. Epub 2011 Apr 12.
- PubMed ID
- 21486038 [ View in PubMed]
- 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 beta(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.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Vortioxetine 5-hydroxytryptamine receptor 1A Protein Humans YesAgonistDetails Vortioxetine 5-hydroxytryptamine receptor 1B Protein Humans YesPartial agonistDetails Vortioxetine 5-hydroxytryptamine receptor 3A Protein Humans YesAntagonistDetails Vortioxetine 5-hydroxytryptamine receptor 7 Protein Humans YesAntagonistDetails Vortioxetine Beta-1 adrenergic receptor Protein Humans UnknownLigandDetails Vortioxetine Sodium-dependent noradrenaline transporter Protein Humans UnknownBlockerDetails Vortioxetine Sodium-dependent serotonin transporter Protein Humans YesInhibitorDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Buspirone 5-hydroxytryptamine receptor 1A Ki (nM) 21 N/A N/A Details Ondansetron 5-hydroxytryptamine receptor 3A IC 50 (nM) 0.09 N/A N/A Details Ondansetron 5-hydroxytryptamine receptor 3A Ki (nM) 2.8 N/A N/A Details