RDS03-94

Last updated

RDS03-94
RDS03-94.svg
Clinical data
Other namesRDS3-094
Identifiers
  • 1-[(2S,6R)-4-[2-[bis(4-fluorophenyl)methylsulfanyl]ethyl]-2,6-dimethylpiperazin-1-yl]propan-2-ol
CAS Number
PubChem CID
ChEMBL
Chemical and physical data
Formula C24H32F2N2OS
Molar mass 434.59 g·mol−1
3D model (JSmol)
  • C[C@@H]1CN(C[C@@H](N1CC(C)O)C)CCSC(C2=CC=C(C=C2)F)C3=CC=C(C=C3)F
  • InChI=1S/C24H32F2N2OS/c1-17-14-27(15-18(2)28(17)16-19(3)29)12-13-30-24(20-4-8-22(25)9-5-20)21-6-10-23(26)11-7-21/h4-11,17-19,24,29H,12-16H2,1-3H3/t17-,18+,19?
  • Key:GVCYHQGCEQPNRF-DFNIBXOVSA-N

RDS03-94, or RDS3-094, is an atypical dopamine reuptake inhibitor that was derived from the wakefulness-promoting agent modafinil. [1] [2] [3] [4]

It has substantially higher affinity and potency in terms of dopamine transporter (DAT) inhibition than modafinil (Ki = 39.4 nM vs. 8,160 nM) whilst retaining the atypical DAT blocker profile of modafinil. [1] [2] However, RDS03-94 also has high affinity for the sigma σ1 receptor (Ki = 2.19 nM). [2]

RDS03-94 shows some reversal of tetrabenazine-induced motivational deficits in animals and hence may have the capacity to produce pro-motivational effects. [5] [6] However, it appears to be less effective than certain other related agents, like JJC8-088. [6] [5]

RDS03-94 is under development for the treatment of psychostimulant use disorder. [1] The drug was first described in the scientific literature in 2020. [1] [2]

See also

References

  1. 1 2 3 4 Tanda G, Hersey M, Hempel B, Xi ZX, Newman AH (February 2021). "Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder". Current Opinion in Pharmacology. 56: 13–21. doi:10.1016/j.coph.2020.07.007. PMC   8247144 . PMID   32927246. More recently, by introducing the 2,6-dimethyl substitution on the piperazine ring, some improvement in drug-like properties was realized with RDS03-94 [29]. Nevertheless, the piperazine ring remained a metabolically labile functional group and hence a new series of analogues in which it was replaced with an amino-piperidine function was prepared [30]. These new analogues demonstrated superior metabolic stability and are currently being evaluated in rodent models of [psychostimulant use disorder (PSUD)]. In addition, novel heterocyclic-based analogues that may also be promising new leads for PSUD therapeutics have recently been reported [31,32].
  2. 1 2 3 4 Slack RD, Ku TC, Cao J, Giancola JB, Bonifazi A, Loland CJ, et al. (March 2020). "Structure-Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter: Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability". Journal of Medicinal Chemistry. 63 (5): 2343–2357. doi:10.1021/acs.jmedchem.9b01188. PMC   9617638 . PMID   31661268.
  3. ↑ Ku TC, Cao J, Won SJ, Guo J, Camacho-Hernandez GA, Okorom AV, et al. (February 2024). "Series of (([1,1'-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity". ACS Pharmacology & Translational Science. 7 (2): 515–532. doi:10.1021/acsptsci.3c00322. PMC   10863442 . PMID   38357284.
  4. ↑ Okorom AV, Camacho-Hernandez GA, Salomon K, Lee KH, Ku TC, Cao J, et al. (January 2024). "Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile". Journal of Medicinal Chemistry. 67 (1): 709–727. doi:10.1021/acs.jmedchem.3c02037. PMID   38117239.
  5. 1 2 Ecevitoglu A, Meka N, Rotolo RA, Edelstein GA, Srinath S, Beard KR, et al. (July 2024). "Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors". Neuropsychopharmacology. 49 (8): 1309–1317. doi:10.1038/s41386-024-01826-1. PMC  11224370. PMID   38429498.
  6. 1 2 Meka NM (2022). "Assessment of Effort-related Motivational Effects of Novel Modafinil Analogs from NIDA Laboratories". ProQuest. Retrieved 16 September 2024.
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