(S)-MK-26

(S)-MK-26 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil.^[1][2][3] It is closely related to two other modafinil analogues, (S,S)-CE-158 and (S)-CE-123.^[2][3]

(S)-MK-26

Clinical data
Drug class	Atypical dopamine reuptake inhibitor
Identifiers
CAS Number	2407547-18-4
Chemical and physical data
Formula	C17H13Cl2NOS2
Molar mass	382.32 g·mol−1
3D model (JSmol)	Interactive image
SMILES C1=CC=C(Cl)C=C1C([S@@](=O)CC1SC=NC=1)C1=CC(Cl)=CC=C1
InChI InChI=InChI=1S/C17H13Cl2NOS2/c18-14-5-1-3-12(7-14)17(13-4-2-6-15(19)8-13)23(21)10-16-9-20-11-22-16/h1-9,11,17H,10H2/t23-/m0/s1 Key:WOJHQJWZRIRCQE-QHCPKHFHSA-N

(S)-MK-26 has markedly improved potency and selectivity as a blocker of the dopamine transporter (DAT) compared to modafinil (IC₅₀Tooltip half-maximal inhibitory concentration = 49 nM vs. 6,400 nΜ; 130-fold difference).^[3]

It has pro-motivational effects in animals and reverses tetrabenazine-induced motivational deficits and depression-like behavior.^[1][3] The drug dose-dependently increases extracellular dopamine levels in the nucleus accumbens and prefrontal cortex, does not modify locomotor activity (a measure of psychostimulant-like effect), and slightly enhances spatial memory in animals.^[2][3]

There has been interest in (S)-MK-26 as a potential treatment for depression, psychostimulant use disorder (PSUD), Alzheimer's disease, and aging-related disorders.^[2][4][3] It was first described by 2022.^[3]

See also

• List of modafinil analogues and derivatives
• MRZ-9547
• PRX-14040

References

1. Salamone JD, Correa M (January 2024). "The Neurobiology of Activational Aspects of Motivation: Exertion of Effort, Effort-Based Decision Making, and the Role of Dopamine". Annu Rev Psychol. 75: 1–32. doi:10.1146/annurev-psych-020223-012208. hdl:10234/207207. PMID 37788571.
2. Hersey M, Bartole MK, Jones CS, Newman AH, Tanda G (July 2023). "Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors". Molecules. 28 (13): 5270. doi:10.3390/molecules28135270. PMC 10343811. PMID 37446929.
3. Kouhnavardi S, Ecevitoglu A, Dragačević V, Sanna F, Arias-Sandoval E, Kalaba P, Kirchhofer M, Lubec J, Niello M, Holy M, Zehl M, Pillwein M, Wackerlig J, Murau R, Mohrmann A, Beard KR, Sitte HH, Urban E, Sagheddu C, Pistis M, Plasenzotti R, Salamone JD, Langer T, Lubec G, Monje FJ (June 2022). "A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions". Biomolecules. 12 (7): 881. doi:10.3390/biom12070881. PMC 9312958. PMID 35883437.
4. Shaikh A, Ahmad F, Teoh SL, Kumar J, Yahaya MF (2023). "Targeting dopamine transporter to ameliorate cognitive deficits in Alzheimer's disease". Front Cell Neurosci. 17: 1292858. doi:10.3389/fncel.2023.1292858. PMC 10679733. PMID 38026688.