WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H532250
CAS#: 1488362-55-5 (S-isomer)
Description: ML375, also known as VU0483253, is a potent, selective and CNS penetrant M5 negative allosteric modulator (NAM). ML375 is a highly selective M5 NAM with submicromolar potency (human M5 IC50 = 300 nM, rat M5 IC50 = 790 nM, M1-M4 IC50 > 30 μM), excellent multispecies PK, high CNS penetration, and enantiospecific inhibition. ML375 show good rat and cyno pharmacokinetics to support in vivo studies in rodents and non-human primates. Note: ML375 is an analogue of VU-6008667.
Hodoodo Cat#: H532250
Name: ML375
CAS#: 1488362-55-5 (S-isomer)
Chemical Formula: C23H15ClF2N2O2
Exact Mass: 424.08
Molecular Weight: 424.832
Elemental Analysis: C, 65.03; H, 3.56; Cl, 8.34; F, 8.94; N, 6.59; O, 7.53
Related CAS #: 1488362-55-5 (S-isomer) 1488362-56-6 (R-isomer)
Synonym: 1400W; 1400W, ML375; ML 375; ML-375; VU0483253; VU-0483253; VU 0483253;
IUPAC/Chemical Name: (9bS)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydroimidazo[2,1-a]isoindol-5-one
InChi Key: GXBAKXRLQAPKEE-QHCPKHFHSA-N
InChi Code: InChI=1S/C23H15ClF2N2O2/c24-16-8-6-15(7-9-16)23-18-4-2-1-3-17(18)22(30)28(23)12-11-27(23)21(29)14-5-10-19(25)20(26)13-14/h1-10,13H,11-12H2/t23-/m0/s1
SMILES Code: O=C1N2[C@@](N(C(C3=CC=C(F)C(F)=C3)=O)CC2)(C4=CC=C(Cl)C=C4)C5=C1C=CC=C5
Appearance: Solid powder
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: >2 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
More Info:
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| In vitro activity: | |
| In vivo activity: |
The following data is based on the product molecular weight 424.83 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: | |
| In vitro protocol: | |
| In vivo protocol: |
1: Teal LB, Bubser M, Duncan E, Gould RW, Lindsley CW, Jones CK. Selective M5 muscarinic acetylcholine receptor negative allosteric modulator VU6008667 blocks acquisition of opioid self-administration. Neuropharmacology. 2023 Apr 1;227:109424. doi: 10.1016/j.neuropharm.2023.109424. Epub 2023 Jan 28. PMID: 36720403.
2: Burger WAC, Gentry PR, Berizzi AE, Vuckovic Z, van der Westhuizen ET, Thompson G, Yeasmin M, Lindsley CW, Sexton PM, Langmead CJ, Tobin AB, Christopoulos A, Valant C, Thal DM. Identification of a Novel Allosteric Site at the M5 Muscarinic Acetylcholine Receptor. ACS Chem Neurosci. 2021 Aug 18;12(16):3112-3123. doi: 10.1021/acschemneuro.1c00383. Epub 2021 Aug 5. PMID: 34351123.
3: Walker LC, Huckstep KL, Chen NA, Hand LJ, Lindsley CW, Langmead CJ, Lawrence AJ. Muscarinic M4 and M5 receptors in the ventral subiculum differentially modulate alcohol seeking versus consumption in male alcohol-preferring rats. Br J Pharmacol. 2021 Sep;178(18):3730-3746. doi: 10.1111/bph.15513. Epub 2021 Jun 3. PMID: 33942300.
4: Gould RW, Gunter BW, Bubser M, Matthews RT, Teal LB, Ragland MG, Bridges TM, Garrison AT, Winder DG, Lindsley CW, Jones CK. Acute Negative Allosteric Modulation of M5 Muscarinic Acetylcholine Receptors Inhibits Oxycodone Self-Administration and Cue-Induced Reactivity with No Effect on Antinociception. ACS Chem Neurosci. 2019 Aug 21;10(8):3740-3750. doi: 10.1021/acschemneuro.9b00274. Epub 2019 Jul 24. PMID: 31268669; PMCID: PMC7383364.
5: Berizzi AE, Perry CJ, Shackleford DM, Lindsley CW, Jones CK, Chen NA, Sexton PM, Christopoulos A, Langmead CJ, Lawrence AJ. Muscarinic M5 receptors modulate ethanol seeking in rats. Neuropsychopharmacology. 2018 Jun;43(7):1510-1517. doi: 10.1038/s41386-017-0007-3. Epub 2018 Feb 5. PMID: 29483658; PMCID: PMC5983544.
6: Gunter BW, Gould RW, Bubser M, McGowan KM, Lindsley CW, Jones CK. Selective inhibition of M5 muscarinic acetylcholine receptors attenuates cocaine self-administration in rats. Addict Biol. 2018 Sep;23(5):1106-1116. doi: 10.1111/adb.12567. Epub 2017 Oct 18. PMID: 29044937; PMCID: PMC5906200.
7: McGowan KM, Nance KD, Cho HP, Bridges TM, Conn PJ, Jones CK, Lindsley CW. Continued optimization of the M5 NAM ML375: Discovery of VU6008667, an M5 NAM with high CNS penetration and a desired short half-life in rat for addiction studies. Bioorg Med Chem Lett. 2017 Mar 15;27(6):1356-1359. doi: 10.1016/j.bmcl.2017.02.020. Epub 2017 Feb 13. PMID: 28237763; PMCID: PMC5508536.
8: Sakkal LA, Rajkowski KZ, Armen RS. Prediction of consensus binding mode geometries for related chemical series of positive allosteric modulators of adenosine and muscarinic acetylcholine receptors. J Comput Chem. 2017 Jun 5;38(15):1209-1228. doi: 10.1002/jcc.24728. Epub 2017 Jan 28. PMID: 28130813; PMCID: PMC5403616.
9: Geanes AR, Cho HP, Nance KD, McGowan KM, Conn PJ, Jones CK, Meiler J, Lindsley CW. Ligand-based virtual screen for the discovery of novel M5 inhibitor chemotypes. Bioorg Med Chem Lett. 2016 Sep 15;26(18):4487-4491. doi: 10.1016/j.bmcl.2016.07.071. Epub 2016 Jul 30. PMID: 27503678; PMCID: PMC4996684.
10: Berizzi AE, Gentry PR, Rueda P, Den Hoedt S, Sexton PM, Langmead CJ, Christopoulos A. Molecular Mechanisms of Action of M5 Muscarinic Acetylcholine Receptor Allosteric Modulators. Mol Pharmacol. 2016 Oct;90(4):427-36. doi: 10.1124/mol.116.104182. Epub 2016 Jul 26. PMID: 27461343.
11: Kurata H, Gentry PR, Kokubo M, Cho HP, Bridges TM, Niswender CM, Byers FW, Wood MR, Daniels JS, Conn PJ, Lindsley CW. Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges. Bioorg Med Chem Lett. 2015 Feb 1;25(3):690-4. doi: 10.1016/j.bmcl.2014.11.082. Epub 2014 Dec 13. PMID: 25542588; PMCID: PMC4535335.
12: Gentry PR, Kokubo M, Bridges TM, Daniels JS, Niswender CM, Smith E, Chase P, Hodder PS, Rosen H, Conn PJ, Engers J, Brewer KA, Wood MR, Lindsley CW. Development of the First Potent, Selective and CNS penetrant M5 Negative Allosteric Modulator (NAM). 2013 Dec 9 [updated 2014 Sep 18]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010–. PMID: 25506971.
13: Gentry PR, Kokubo M, Bridges TM, Kett NR, Harp JM, Cho HP, Smith E, Chase P, Hodder PS, Niswender CM, Daniels JS, Conn PJ, Wood MR, Lindsley CW. Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenz oyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375). J Med Chem. 2013 Nov 27;56(22):9351-5. doi: 10.1021/jm4013246. Epub 2013 Nov 13. PMID: 24164599; PMCID: PMC3876027.
14: Merki-Feld GS, Lebeda E, Hogg B, Keller PJ. The incidence of actinomyces- like organisms in Papanicolaou-stained smears of copper- and levonorgestrel- releasing intrauterine devices. Contraception. 2000 Jun;61(6):365-8. doi: 10.1016/s0010-7824(00)00121-9. PMID: 10958879.
15: Souza JP, Andrade AT, Pizarro E. Perda sanguinea menstrual e estoques de ferro do organismo -- estudo comparativo entre o DIU Multiload-375 e o anel vaginal de levonorgestrel [Menstrual blood loss and body iron stores: comparative study between a Multiload-375 IUD and a levonorgestrel vaginal ring]. Bol Cent Biol Reprod. 1991;10(1):26-32. Portuguese. PMID: 12318141.
