Tedatioxetine

Overview

Tedatioxetine (developmental code name Lu AA24530) is an experimental antidepressant developed by H. Lundbeck A/S for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). It acts as a triple reuptake inhibitor (TRI) with preference for serotonin and norepinephrine over dopamine, and as an antagonist at 5-HT2A, 5-HT2C, 5-HT3, and α1A-adrenergic receptors. In 2007 Lundbeck and Takeda entered into a partnership that included tedatioxetine but was focused on another, more advanced Lundbeck drug candidate, vortioxetine.[1] WP

Tedatioxetine reached Phase II clinical trials for major depressive disorder in 2009 but was discontinued in May 2016, with no further development reported. Despite its termination, data from clinical studies have provided valuable insights into CYP2D6 metabolism and pharmacogenetics.[2–5] WP

Pharmacology

Pharmacokinetics

Tedatioxetine is a sensitive substrate of the CYP2D6 enzyme, exhibiting significant interindividual variability in metabolism due to genetic polymorphisms. A 2021 population pharmacokinetic (popPK) study involving 578 subjects quantified CYP2D6 activity across genotypes, reporting mean oral clearances of 18 L/h for poor metabolizers (PMs), 40 L/h for intermediate metabolizers (IMs), 60 L/h for normal metabolizers (NMs), and 77 L/h for ultrarapid metabolizers (UMs). Approximately 80% of clearance is mediated by CYP2D6.[6] WP

The drug has a slow absorption rate, with a median time to maximum plasma concentration (tmax) of 5–6 hours. Its primary metabolite, Lu AA37208, shows a similar or shorter tmax, indicating presystemic metabolism. The study highlighted low enzyme activity for CYP2D6*17 and *41 alleles, suggesting a need to revise activity scores for personalized dosing.[6] WP

CYP2D6 variability posed challenges for consistent dosing across populations, particularly for CYP2D6*17 and *41 carriers.[6] WP

Pharmacodynamics

Tedatioxetine is a multimodal antidepressant that inhibits the reuptake of serotonin, norepinephrine, and dopamine, with a preference for serotonin and norepinephrine (5-HT > NE > DA). It also antagonizes 5-HT2A, 5-HT2C, and 5-HT₃ serotonin receptors and α1A-adrenergic receptor antagonist, potentially enhancing monoamine transmission and reducing side effects like nausea associated with 5-HT₃ activation.[7–11] WP

Preclinical studies suggest this profile may improve efficacy in MDD by targeting multiple neurotransmitter systems.[12] WP

The compound’s receptor antagonism, particularly at 5-HT2C and 5-HT3, may contribute to its anxiolytic properties, making it a candidate for GAD treatment. Its triple reuptake inhibition distinguishes it from selective serotonin reuptake inhibitors (SSRIs), potentially offering broader symptom relief in complex mood disorders.[13] WP

Chemistry

Formula

C18H21NS PC

CAS number

508233-95-2 PC

Molar mass (g/mol)

283.4 PC

IUPAC name (computed by PubChem)

4-[2-(4-methylphenyl)sulfanylphenyl]piperidine PC

SMILES

CC1=CC=C(C=C1)SC2=CC=CC=C2C3CCNCC3 PC

InChIKey

CVASBKDYSQKLSO-UHFFFAOYSA-N PC

PubChem CID

9878913

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Other Beaulieu D. Lundbeck, Takeda enter strategic alliance for mood disorder, anxiety drugs]. 5 September 2007
2. Other TEDATIOXETINE
3. Other Pipeline of Lundbeck
4. Other Tedatioxetine
5. Journal / agency Tedatioxetine
6. Journal / agency Frederiksen T, Areberg J, Schmidt E, Stage T, Brøsen K. Cytochrome P450 2D6 genotype–phenotype characterization through population pharmacokinetic modeling of tedatioxetine. ChemBioChem. Sep 2021. doi:10.1002/psp4.12663 · PMID 34107164 · PMC8376138
7. Other Tedatioxetine (Lu AA24530)
8. Other 4-[2-(4-methylphenylsulfanyd-phenyl] piperidine with combined serotonin and norepinephrine reuptake inhibition for the treatment of adhd, melancholia, treatment resistant depression or residual symptoms in depression
9. Other Stahl SM. Depression and bipolar disorder: Stahl's essential psychopharmacology. 19 May 2008
10. Other Stolerman IP. Encyclopedia of Psychopharmacology. 30 August 2010
11. Other Lu AA24530 shows positive results in major depressive disorder phase II study. 2 July 2009
12. Other Tedatioxetine (Major Depressive Disorder) - Forecast and Market Analysis to 2023. 24 June 2014
13. Journal / agency Javelot H. Psychopharmacology of anxiety and depression: Historical aspects, current treatments and perspectives. Trends in Biochemical Sciences. Nov 2015. doi:10.1016/j.pharma.2015.09.002 · PMID 26481500 · PMC4630146

Text and values on this page are quoted from Wikipedia (CC BY-SA 4.0), PubChem (public domain). Each value links to the exact revision it came from.