Synonym
AUT-1; AUT 1; AUT1
IUPAC/Chemical Name
(5R)-5-Ethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione
InChi Key
AMAOXEGBJHLCSF-CQSZACIVSA-N
InChi Code
InChI=1S/C18H19N3O4/c1-4-14-17(22)21(18(23)20-14)12-6-8-16(19-10-12)25-13-7-5-11(2)15(9-13)24-3/h5-10,14H,4H2,1-3H3,(H,20,23)/t14-/m1/s1
SMILES Code
O=C1N(C2=CC=C(OC3=CC=C(C)C(OC)=C3)N=C2)C([C@@H](CC)N1)=O
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>3 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
AUT1 is a Kv3 potassium channel modulator, with pEC50s of 5.33 and 5.31 for human recombinant Kv3.1b and Kv3.2a, respectively.
In vitro activity:
Whole cell voltage clamp recordings were performed on DCN fusiform cells, which were held at −60 mV. Stepping to voltages above −30 mV evoked large non-inactivating outward K+ currents (Fig. 2A, current at + 0 mV = 16.54 ± 10 nA, n = 4) which were reduced by approximately 50% by the perfusion of 0.5 mM TEA (Fig. 2A , 8.1 ± 3.6 nA, n = 4, P = 0.04, paired t-test). Slices were pre-incubated with AUT1 (10 μM) for 1 h. This resulted in a 65% increase in the amplitude of the K+ current at 0 mV (Fig. 2B, Control: 6.4 ± 2.3 nA, n = 6; AUT1: 10.6 ± 6.3 nA, n = 6, P = 0.02, one-sided Mann-Whitney test).
Reference: Neuropharmacology. 2018 May 1; 133: 319–333. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869058/
In vivo activity:
WT mice, however, that received AUT1 before amphetamine, exhibited attenuation in amphetamine-induced hyperactivity with the effects most notable at the 60 and 100 mg/kg doses. Two-way ANOVA revealed a significant main effect of treatment on locomotor activity (F(4, 67)=22.37, p<0.0001) and a genotype × treatment interaction (F(4, 67)=2.28, p=0.07; Figure 2b). At the highest dose of 100 mg/kg, AUT1 significantly decreased locomotor activity in both WT and Kv3.1-null mice before amphetamine injection, possibly indicating a nonspecific sedative effect at this dose (Figure 2a). AUT1, however, was not effective at reducing amphetamine-induced hyperactivity in mice lacking Kv3.1 channels, even at these high doses (Figure 2b and Supplementary Figure S1), arguing against a purely sedative effect. This suggests that functional Kv3.1 channels are required for the effects of AUT1 on amphetamine-induced hyperactivity. Notably, this was confirmed by repeating the experiment using Kv3.2 knockout mice where AUT1 was as effective at preventing hyperactivity as in WT mice (F(2, 24)=12.73, p=0.0002; Supplementary Figure S2). Collectively, this suggests that Kv3.1 channels (and not Kv3.2) are necessary for AUT1 mechanism of action in this model.
Reference: Neuropsychopharmacology. 2018 Jan; 43(2): 435–444. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729564/
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO:PBS (pH 7.2) (1:4) |
0.2 |
0.59 |
| DMF |
30.0 |
87.88 |
| Ethanol |
5.0 |
14.65 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
341.37
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Olsen T, Capurro A, Pilati N, Large CH, Hamann M. Kv3 K+ currents contribute to spike-timing in dorsal cochlear nucleus principal cells. Neuropharmacology. 2018 May 1;133:319-333. doi: 10.1016/j.neuropharm.2018.02.004. Epub 2018 Feb 5. PMID: 29421326; PMCID: PMC5869058.
2. Rosato-Siri MD, Zambello E, Mutinelli C, Garbati N, Benedetti R, Aldegheri L, Graziani F, Virginio C, Alvaro G, Large CH. A Novel Modulator of Kv3 Potassium Channels Regulates the Firing of Parvalbumin-Positive Cortical Interneurons. J Pharmacol Exp Ther. 2015 Sep;354(3):251-60. doi: 10.1124/jpet.115.225748. Epub 2015 Jun 17. PMID: 26085652.
3. Parekh PK, Sidor MM, Gillman A, Becker-Krail D, Bettelini L, Arban R, Alvaro GS, Zambello E, Mutinelli C, Huang Y, Large CH, McClung CA. Antimanic Efficacy of a Novel Kv3 Potassium Channel Modulator. Neuropsychopharmacology. 2018 Jan;43(2):435-444. doi: 10.1038/npp.2017.155. Epub 2017 Aug 31. PMID: 28857068; PMCID: PMC5729564.
In vitro protocol:
1. Olsen T, Capurro A, Pilati N, Large CH, Hamann M. Kv3 K+ currents contribute to spike-timing in dorsal cochlear nucleus principal cells. Neuropharmacology. 2018 May 1;133:319-333. doi: 10.1016/j.neuropharm.2018.02.004. Epub 2018 Feb 5. PMID: 29421326; PMCID: PMC5869058.
2. Rosato-Siri MD, Zambello E, Mutinelli C, Garbati N, Benedetti R, Aldegheri L, Graziani F, Virginio C, Alvaro G, Large CH. A Novel Modulator of Kv3 Potassium Channels Regulates the Firing of Parvalbumin-Positive Cortical Interneurons. J Pharmacol Exp Ther. 2015 Sep;354(3):251-60. doi: 10.1124/jpet.115.225748. Epub 2015 Jun 17. PMID: 26085652.
In vivo protocol:
1. Parekh PK, Sidor MM, Gillman A, Becker-Krail D, Bettelini L, Arban R, Alvaro GS, Zambello E, Mutinelli C, Huang Y, Large CH, McClung CA. Antimanic Efficacy of a Novel Kv3 Potassium Channel Modulator. Neuropsychopharmacology. 2018 Jan;43(2):435-444. doi: 10.1038/npp.2017.155. Epub 2017 Aug 31. PMID: 28857068; PMCID: PMC5729564.
1: Rosato-Siri MD, Zambello E, Mutinelli C, Garbati N, Benedetti R, Aldegheri L, Graziani F, Virginio C, Alvaro G, Large CH. A Novel Modulator of Kv3 Potassium Channels Regulates the Firing of Parvalbumin-Positive Cortical Interneurons. J Pharmacol Exp Ther. 2015 Sep;354(3):251-60. doi: 10.1124/jpet.115.225748. Epub 2015 Jun 17. PubMed PMID: 26085652.
2: Olsen T, Capurro A, Pilati N, Large CH, Hamann M. Kv3 K(+) currents contribute to spike-timing in dorsal cochlear nucleus principal cells. Neuropharmacology. 2018 May 1;133:319-333. doi: 10.1016/j.neuropharm.2018.02.004. Epub 2018 Feb 5. PubMed PMID: 29421326; PubMed Central PMCID: PMC5869058.
3: Parekh PK, Sidor MM, Gillman A, Becker-Krail D, Bettelini L, Arban R, Alvaro GS, Zambello E, Mutinelli C, Huang Y, Large CH, McClung CA. Antimanic Efficacy of a Novel Kv3 Potassium Channel Modulator. Neuropsychopharmacology. 2018 Jan;43(2):435-444. doi: 10.1038/npp.2017.155. Epub 2017 Aug 31. PubMed PMID: 28857068; PubMed Central PMCID: PMC5729564.
4: Brown MR, El-Hassar L, Zhang Y, Alvaro G, Large CH, Kaczmarek LK. Physiological modulators of Kv3.1 channels adjust firing patterns of auditory brain stem neurons. J Neurophysiol. 2016 Jul 1;116(1):106-21. doi: 10.1152/jn.00174.2016. Epub 2016 Apr 6. PubMed PMID: 27052580; PubMed Central PMCID: PMC4961756.
