KM822
KM822 is a dopamine transporter (DAT) inhibitor with an IC50 of 2.2 μM against hDAT and an IC50 of 10.4 μM against C. elegans DAT-1. KM822 binds to the allosteric A2 site in the extracellular vestibule of outward-facing DAT, reduces the affinity of psychostimulants and phenethylamine psychostimulants for DAT, and inhibits dopamine transport function. KM822 attenuates the behaviors induced by psychostimulants and phenethylamine psychostimulants in planarians and C. elegans, does not induce locomotor effects on its own, and exhibits specificity for DAT. KM822 can serve as a molecular probe for investigating the allosteric regulation of DAT function. KM822 is applicable to studies related to psychostimulant use disorders.
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- CAS No.: 497926-94-0
- Formule: C21H22N6O3S2
- Masse moléculaire:470.57
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Activité biologique
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hDAT 2.2 μM (IC50) |
DAT-1 10.4 μM (IC50) |
KM822 (100 ns) binds to the allosteric subsite S2-II of human dopamine transporter (hDAT) in the outward-facing open conformation, coordinated by residues W84, R85, F217, D476, H477, and Y548[1].
KM822 non-competitively inhibits dopamine uptake by human dopamine transporter (hDAT) and reduces the affinity of a controlled tropane alkaloid psychostimulant for hDAT[1].
KM822 potently and selectively inhibits hDAT-mediated dopamine reuptake with an IC50 of 3.7 μM, showing 30-fold and 50-fold lower potency for hNET and hSERT, respectively, in stably transfected MDCK cells[2].
KM822 (1-5 μM; 10 min uptake) non-competitively inhibits hDAT-mediated dopamine uptake in transiently transfected COS-7 cells, reducing Vmax without significantly altering apparent dopamine Km at concentrations of 1 μM and 5 μM[2].
KM822 (10 min pre-incubation at 4°C, followed by 10 min MTSEA-biotin labeling at 4°C) dose-dependently protects the W84C cysteine mutant of hDAT from MTSEA-biotin labeling in transiently transfected HEK-293 cells, with an IC50 of 0.45 μM, confirming direct interaction with the W84 residue in the allosteric site[2].
KM822 (10 min pre-incubation, followed by 10 min uptake) preferentially binds to the outward-facing conformation of hDAT, as its potency is unchanged in hDATY156F mutants but reduced three-fold in hDATY335A mutants in transiently transfected COS-7 cells[2].
KM822 (1-5 μM) dose-dependently reduces the potency of Phenethylamine Tropane for inhibiting hDAT-mediated dopamine reuptake in transiently transfected COS-7 cells, increasing phenethylamine tropane's IC50 from 1.2 μM to 4.2 μM and 8.1 μM at concentrations of 1 μM and 5 μM, respectively[2].
KM822 binds with high affinity to the conserved A2 allosteric pocket in the OFo conformer of C. elegans DAT-1, with no detectable binding to the IFo conformer[3].
KM822 (10-3-103 μM; 10 min pre-incubation) inhibits dopamine uptake via C. elegans DAT-1 (IC50 = 10.4 μM) and human DAT (IC50 = 2.2 μM) in transiently transfected COS-7 cells[3].
KM822 (20 μM) reduces the affinity of amphetamine for DAT-1 in transiently transfected COS-7 cells, increasing amphetamine's IC50 for dopamine uptake inhibition from 1.1 μM to 3.4 μM[3].
KM822 (20 μM) reduces the affinity of psychostimulant tropane alkaloid for DAT-1 in transiently transfected COS-7 cells, increasing psychostimulant tropane alkaloid's IC50 for dopamine uptake inhibition from 9.6 μM to 128 μM[3].
KM822 (150 ns) selectively binds to the allosteric A2 site in the extracellular vestibule of the outward-facing open conformation of human DAT, with distinct residue interactions in two stable binding poses[4].
KM822 (20 µM; 10 min) directly binds in the vicinity of the W84 residue in human dopamine transporter, confirming interaction with the allosteric A2 site in HEK-293 cells expressing DAT-XC/W84C[4].
KM822 (10 min) preferentially binds the outward-facing conformation of human dopamine transporter, as its potency is unchanged in COS-7 cells expressing outward-facing shifted Y156F-hDAT but reduced in cells expressing inward-facing shifted Y335A-hDAT[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
KM822 attenuates amphetamine-induced behavior in C. elegans via specific allosteric modulation of DAT, as evidenced by the lack of effect in DAT-deficient worms[1].
KM822 (20 µM; in water bath; continuous exposure during observation periods) specifically inhibits DAT-mediated psychostimulant-induced locomotion in planarians, with no effect on nicotine-induced or baseline locomotion[2].
KM822 (10-500 μM; acute exposure in swimming medium; 10 minutes) acutely suppresses Amphetamine-induced swimming-induced paralysis in wild-type Caenorhabditis elegans at a dose of 250 μM, with no effect on baseline swimming behavior at concentrations up to 500 μM[3].
KM822 (250 μM; acute exposure in swimming medium; 10 minutes) does not suppress amphetamine-induced swimming-induced paralysis in Caenorhabditis elegans, confirming its effects are DAT-1-dependent[3].
KM822 (250 μM; acute exposure in swimming medium; 10 minutes) suppresses amphetamine-induced swimming-induced paralysis in Caenorhabditis elegans, indicating its effects are independent of LGC-55[3].
KM822 (250 μM; acute exposure in swimming medium; 10 minutes) does not suppress Amphetamine-induced swimming-induced paralysis in DAT-1/LGC-55 double-deficient Caenorhabditis elegans, confirming its effects require DAT-1[3].
KM822 (250 μM; acute exposure in swimming medium; 10 minutes) does not suppress β-phenylethylamine-induced swimming-induced paralysis in wild-type Caenorhabditis elegans, confirming its effects are not mediated through LGC-55[3].
KM822 (250 μM; acute exposure in swimming medium; 10 minutes) does not suppress Nisoxetine (HY-B1704)-induced swimming-induced paralysis in wild-type Caenorhabditis elegans, consistent with its lack of effect on Nisoxetine-DAT-1 interactions in vitro[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Dugesia dorotocephala[2]
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Dosage:20 µM
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Administration:in water bath; continuous exposure during observation periods
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Result:Completely blocked the stimulated locomotion elicited by 10 µM cocaine and 5 µM amphetamine, resulting in locomotion comparable to vehicle-treated planarians.
Did not block 20 µM nicotine-elicited locomotion.
Had no effect on baseline locomotion when administered alone.
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Animal Model:N2 Bristol (wild-type, L4 hermaphrodites)[3]
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Dosage:10 μM, 75 μM, 150 μM, 200 μM, 250 μM, 350 μM, 500 μM (alone); 250 μM (co-administered with 150 μM, 250 μM, 300 μM, 500 μM amphetamine)
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Administration:acute exposure in swimming medium; 10 minutes
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Result:Exhibited no statistically significant effect on swimming behavior of wild-type worms at all tested concentrations.
Produced significantly higher swimming fractions (reduced Swip) when co-administered with 250 μM, 300 μM, or 500 μM amphetamine compared to amphetamine alone (****, P < 0.0001).
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Animal Model:dat-1(ok157) (DAT-1 loss-of-function, L4 hermaphrodites)[3]
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Dosage:250 μM (alone); 250 μM (co-administered with 300 μM amphetamine)
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Administration:acute exposure in swimming medium; 10 minutes
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Result:Exhibited no statistically significant effect on swimming behavior of dat-1(ok157) worms when administered alone.
Showed no statistically significant effect on amphetamine-induced Swip in dat-1(ok157) worms when co-administered with 300 μM amphetamine.
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Animal Model:lgc-55(n4331) (LGC-55 loss-of-function, L4 hermaphrodites)[3]
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Dosage:250 μM (co-administered with 300 μM amphetamine)
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Administration:acute exposure in swimming medium; 10 minutes
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Result:Suppressed amphetamine-induced Swip in lgc-55(n4331) worms even more effectively than in wild-type N2 worms (****, P < 0.0001).
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Animal Model:dat-1(ok157); lgc-55(n4331) (double loss-of-function, L4 hermaphrodites)[3]
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Dosage:250 μM (co-administered with 300 μM amphetamine)
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Administration:acute exposure in swimming medium; 10 minutes
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Result:Exhibited no statistically significant effect on amphetamine-induced Swip in dat-1(ok157); lgc-55(n4331) double mutant worms.
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Animal Model:N2 Bristol (wild-type, L4 hermaphrodites)[3]
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Dosage:250 μM (co-administered with 1 mM β-phenylethylamine)
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Administration:acute exposure in swimming medium; 10 minutes
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Result:Exhibited no statistically significant effect on β-phenylethylamine-induced Swip in wild-type worms.
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Animal Model:N2 Bristol (wild-type, L4 hermaphrodites)[3]
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Dosage:250 μM (co-administered with 2.5 μM or 5 μM nisoxetine)
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Administration:acute exposure in swimming medium; 10 minutes
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Result:Exhibited no statistically significant effect on nisoxetine-induced Swip at either tested nisoxetine concentration.
Chemical Information
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CAS No. 497926-94-0
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Masse moléculaire 470.57
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Formule C21H22N6O3S2
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SMILES
O=C(C)NC1=CC=C(S(=O)(NCCSC2=NC3=C(C(C=C(CC)C=C4)=C4N3)N=N2)=O)C=C1
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
[1]. Nguyen H, et al. Allosteric modulation of serotonin and dopamine transporters: New insights from computations and experiments. Current research in physiology. 2024;7:100125. [Content Brief]
[2]. Aggarwal S, et al. Identification of a Novel Allosteric Modulator of the Human Dopamine Transporter. ACS chemical neuroscience. 2019 Aug 21;10(8):3718-3730. [Content Brief]
[3]. Refai O, et al. Allosteric Modulator KM822 Attenuates Behavioral Actions of Amphetamine in Caenorhabditis elegans through Interactions with the Dopamine Transporter DAT-1. Mol Pharmacol. 2022 Mar;101(3):123-131. [Content Brief]
[4]. Aggarwal S, et al. Functional Characterization of the Dopaminergic Psychostimulant Sydnocarb as an Allosteric Modulator of the Human Dopamine Transporter. Biomedicines. 2021 Jun 02;9(6):634. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
KM822 Related Classifications
HY-128319 Related Classifications
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