Synonym
VU0119498, VU 0119498, VU-0119498
IUPAC/Chemical Name
1-[(4-bromophenyl)methyl]indole-2,3-dione
InChi Key
DELLOEULSHGYCG-UHFFFAOYSA-N
InChi Code
InChI=1S/C15H10BrNO2/c16-11-7-5-10(6-8-11)9-17-13-4-2-1-3-12(13)14(18)15(17)19/h1-8H,9H2
SMILES Code
O=C1N(CC2=CC=C(Br)C=C2)C3=C(C=CC=C3)C1=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
>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
Biological target:
VU0119498 is a M1 muscarinic receptor agonist (EC50 = 3.1 μM) and pan mAChR M3, M5 positive allosteric modulator (PAM).
In vitro activity:
Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca(2+) mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC(50) of approximately 1.16 microM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity.
Reference: Bridges TM, Marlo JE, Niswender CM, Jones CK, Jadhav SB, Gentry PR, Plumley HC, Weaver CD, Conn PJ, Lindsley CW. Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins. J Med Chem. 2009 Jun 11;52(11):3445-8. doi: 10.1021/jm900286j. PMID: 19438238; PMCID: PMC3875304.
In vivo activity:
In this study, VU0119498, a drug known to act as a PAM at M3Rs, significantly augmented ACh-induced insulin release from cultured β cells and mouse and human pancreatic islets. This stimulatory effect was absent in islets prepared from mice lacking M3Rs, indicative of the involvement of M3Rs. VU0119498 treatment of wild-type mice caused a significant increase in plasma insulin levels, accompanied by a striking improvement in glucose tolerance. These effects were mediated by β-cell M3Rs, since they were absent in mutant mice selectively lacking M3Rs in β cells. Moreover, acute VU0119498 treatment of obese, glucose-intolerant mice triggered enhanced insulin release and restored normal glucose tolerance. Interestingly, doses of VU0119498 that led to pronounced improvements in glucose homeostasis did not cause any significant side effects due to activation of M3Rs expressed by other peripheral cell types. Taken together, the data from this proof-of-concept study strongly suggest that M3R PAMs may become clinically useful as novel antidiabetic agents.
Reference: Zhu L, Rossi M, Cohen A, Pham J, Zheng H, Dattaroy D, Mukaibo T, Melvin JE, Langel JL, Hattar S, Matschinsky FM, Appella DH, Doliba NM, Wess J. Allosteric modulation of β-cell M3 muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese mice. Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18684-18690. doi: 10.1073/pnas.1904943116. Epub 2019 Aug 26. PMID: 31451647; PMCID: PMC6744902.
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
50.0 |
158.15 |
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
316.15
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:
Bridges TM, Marlo JE, Niswender CM, Jones CK, Jadhav SB, Gentry PR, Plumley HC, Weaver CD, Conn PJ, Lindsley CW. Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins. J Med Chem. 2009 Jun 11;52(11):3445-8. doi: 10.1021/jm900286j. PMID: 19438238; PMCID: PMC3875304.
In vitro protocol:
Bridges TM, Marlo JE, Niswender CM, Jones CK, Jadhav SB, Gentry PR, Plumley HC, Weaver CD, Conn PJ, Lindsley CW. Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins. J Med Chem. 2009 Jun 11;52(11):3445-8. doi: 10.1021/jm900286j. PMID: 19438238; PMCID: PMC3875304.
In vivo protocol:
Zhu L, Rossi M, Cohen A, Pham J, Zheng H, Dattaroy D, Mukaibo T, Melvin JE, Langel JL, Hattar S, Matschinsky FM, Appella DH, Doliba NM, Wess J. Allosteric modulation of β-cell M3 muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese mice. Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18684-18690. doi: 10.1073/pnas.1904943116. Epub 2019 Aug 26. PMID: 31451647; PMCID: PMC6744902.
1: Zhu L, Rossi M, Cohen A, Pham J, Zheng H, Dattaroy D, Mukaibo T, Melvin JE, Langel JL, Hattar S, Matschinsky FM, Appella DH, Doliba NM, Wess J. Allosteric modulation of β-cell M3 muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese mice. Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18684-18690. doi: 10.1073/pnas.1904943116. Epub 2019 Aug 26. PMID: 31451647; PMCID: PMC6744902.
2: Bridges TM, Kennedy JP, Hopkins CR, Conn PJ, Lindsley CW. Heterobiaryl and heterobiaryl ether derived M5 positive allosteric modulators. Bioorg Med Chem Lett. 2010 Oct 1;20(19):5617-22. doi: 10.1016/j.bmcl.2010.08.042. Epub 2010 Aug 12. PMID: 20801651; PMCID: PMC3179183.
3: Bridges TM, Phillip Kennedy J, Noetzel MJ, Breininger ML, Gentry PR, Conn PJ, Lindsley CW. Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part II: development of a potent and highly selective M1 PAM. Bioorg Med Chem Lett. 2010 Mar 15;20(6):1972-5. doi: 10.1016/j.bmcl.2010.01.109. Epub 2010 Feb 1. PMID: 20156687; PMCID: PMC2834874.
4: Bridges TM, Kennedy JP, Cho HP, Breininger ML, Gentry PR, Hopkins CR, Conn PJ, Lindsley CW. Chemical lead optimization of a pan G(q) mAChR M(1), M(3), M(5) positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M(5) PAM. Bioorg Med Chem Lett. 2010 Jan 15;20(2):558-62. doi: 10.1016/j.bmcl.2009.11.089. Epub 2009 Nov 22. PMID: 20004578; PMCID: PMC3177601.
5: Bridges TM, Marlo JE, Niswender CM, Jones CK, Jadhav SB, Gentry PR, Plumley HC, Weaver CD, Conn PJ, Lindsley CW. Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins. J Med Chem. 2009 Jun 11;52(11):3445-8. doi: 10.1021/jm900286j. PMID: 19438238; PMCID: PMC3875304.
