title: Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder.
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.
authors.affiliation: Neuroscience Drug Discovery Denmark, H. Lundbeck A/S , 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark. ban@lundbeck.com
authors.forename: Benny
authors.initials: B
authors.lastname: Bang-Andersen
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruhland
authors.forename: Morten
authors.initials: M
authors.lastname: Jørgensen
authors.forename: Garrick
authors.initials: G
authors.lastname: Smith
authors.forename: Kristen
authors.initials: K
authors.lastname: Frederiksen
authors.forename: Klaus Gjervig
authors.initials: KG
authors.lastname: Jensen
authors.forename: Huailing
authors.initials: H
authors.lastname: Zhong
authors.forename: Søren Møller
authors.initials: SM
authors.lastname: Nielsen
authors.forename: Sandra
authors.initials: S
authors.lastname: Hogg
authors.forename: Arne
authors.initials: A
authors.lastname: Mørk
authors.forename: Tine Bryan
authors.initials: TB
authors.lastname: Stensbøl
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003865:Major Depressive Disorder / Q000188:drug therapy*; D054333:Drug Partial Agonism; D004355:Drug Stability; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1 / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000078784:Vortioxetine; D014981:Xenopus
chemical_list: D000928:Antidepressive Agents; D010879:Piperazines; D044282:Receptor, Serotonin, 5-HT1A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D044406:Receptors, Serotonin, 5-HT3; D011994:Recombinant Proteins; D012701:Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013440:Sulfides; D000078784:Vortioxetine; C104425:serotonin 7 receptor