RDS03-94

{{Short description|Dopamine reuptake inhibitor related to modafinil being developed for stimulant use disorder}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Infobox drug

| drug_name =

| image = RDS03-94.svg

| width = 250px

| caption =

| pronounce =

| tradename =

| Drugs.com =

| MedlinePlus =

| licence_CA =

| licence_EU =

| DailyMedID =

| licence_US =

| pregnancy_AU =

| pregnancy_category =

| dependency_liability =

| addiction_liability =

| routes_of_administration =

| class =

| ATC_prefix =

| ATC_suffix =

| legal_status =

| bioavailability =

| protein_bound =

| metabolism =

| metabolites =

| onset =

| elimination_half-life =

| duration_of_action =

| excretion =

| CAS_number = 2324108-96-3

| CAS_supplemental =

| PubChem = 150357965

| IUPHAR_ligand =

| DrugBank =

| ChemSpiderID =

| UNII =

| KEGG =

| ChEBI =

| ChEMBL = 4636778

| NIAID_ChemDB =

| PDB_ligand =

| synonyms = RDS3-094

| IUPAC_name = 1-[(2S,6R)-4-[2-[bis(4-fluorophenyl)methylsulfanyl]ethyl]-2,6-dimethylpiperazin-1-yl]propan-2-ol

| C=24 | H=32 | F=2 | N=2 | O=1 | S=1

| SMILES = C[C@@H]1CN(C[C@@H](N1CC(C)O)C)CCSC(C2=CC=C(C=C2)F)C3=CC=C(C=C3)F

| StdInChI = 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?

| StdInChIKey = GVCYHQGCEQPNRF-DFNIBXOVSA-N

}}

RDS03-94, or RDS3-094, is an atypical dopamine reuptake inhibitor that was derived from the wakefulness-promoting agent modafinil.{{cite journal | vauthors = Tanda G, Hersey M, Hempel B, Xi ZX, Newman AH | title = Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder | journal = Current Opinion in Pharmacology | volume = 56 | issue = | pages = 13–21 | date = February 2021 | pmid = 32927246 | pmc = 8247144 | doi = 10.1016/j.coph.2020.07.007 | quote = 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]. }}{{cite journal | vauthors = Slack RD, Ku TC, Cao J, Giancola JB, Bonifazi A, Loland CJ, Gadiano A, Lam J, Rais R, Slusher BS, Coggiano M, Tanda G, Newman AH | title = 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 = Journal of Medicinal Chemistry | volume = 63 | issue = 5 | pages = 2343–2357 | date = March 2020 | pmid = 31661268 | pmc = 9617638 | doi = 10.1021/acs.jmedchem.9b01188 }}{{cite journal | vauthors = Ku TC, Cao J, Won SJ, Guo J, Camacho-Hernandez GA, Okorom AV, Salomon KW, Lee KH, Loland CJ, Duff HJ, Shi L, Newman AH | title = Series of (([1,1'-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity | journal = ACS Pharmacology & Translational Science | volume = 7 | issue = 2 | pages = 515–532 | date = February 2024 | pmid = 38357284 | doi = 10.1021/acsptsci.3c00322 | pmc = 10863442 }}{{cite journal | vauthors = Okorom AV, Camacho-Hernandez GA, Salomon K, Lee KH, Ku TC, Cao J, Won SJ, Friedman J, Lam J, Paule J, Rais R, Klein B, Xi ZX, Shi L, Loland CJ, Newman AH | title = 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 = Journal of Medicinal Chemistry | volume = 67 | issue = 1 | pages = 709–727 | date = January 2024 | pmid = 38117239 | doi = 10.1021/acs.jmedchem.3c02037 | pmc = 11959496 }}

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

RDS03-94 shows some reversal of tetrabenazine-induced motivational deficits in animals and hence may have the capacity to produce pro-motivational effects.{{cite journal | vauthors = Ecevitoglu A, Meka N, Rotolo RA, Edelstein GA, Srinath S, Beard KR, Carratala-Ros C, Presby RE, Cao J, Okorom A, Newman AH, Correa M, Salamone JD | title = Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors | journal = Neuropsychopharmacology | volume = 49 | issue = 8 | pages = 1309–1317 | date = July 2024 | pmid = 38429498 | doi = 10.1038/s41386-024-01826-1 | pmc = 11224370 | pmc-embargo-date = July 1, 2025 | url = }}{{cite web | last=Meka | first=Nicolette M | title=Assessment of Effort-related Motivational Effects of Novel Modafinil Analogs from NIDA Laboratories | date = 2022 | website=ProQuest | url=https://www.proquest.com/openview/d653b1e4c5e4c058a518ea85fa74d1ef/1?pq-origsite=gscholar&cbl=18750&diss=y | access-date=16 September 2024}} However, it appears to be less effective than certain other related agents, like JJC8-088.

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