VU 0238429 - CAS 1160247-92-6
Category: Inhibitor
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Molecular Formula:
Molecular Weight:
VU 0238429 is a selective positive allosteric modulator of M5 muscarinic acetylcholine receptor (EC50 = 1.16, >30 and >30 μM at M5, M1 and M3 receptors, respectively) with no activity at M2 and M4 receptors.
Brife Description:
positive allosteric modulator of M5 muscarinic acetylcholine receptor
≥99% by HPLC
VU0238429, VU 0238429, VU-0238429; 1-(4-Methoxybenzyl)-5-trifluoromethoxyisatin; 1-[(4-methoxyphenyl)methyl]-5-(trifluoromethoxy)indole-2,3-dione
Canonical SMILES:
1.Presynaptic M3 muscarinic cholinoceptors mediate inhibition of excitatory synaptic transmission in area CA1 of rat hippocampus.
de Vin F;Choi SM;Bolognesi ML;Lefebvre RA Brain Res. 2015 Dec 10;1629:260-9. doi: 10.1016/j.brainres.2015.10.031. Epub 2015 Oct 23.
Acetylcholine can modulate hippocampal network function through activation of both nicotinic and muscarinic acetylcholine receptors (mAChRs). All five mAChR subtypes have been identified in the hippocampus. Besides by their involvement in excitability of hippocampal cells, synaptic plasticity and memory, a large body of research has demonstrated the involvement of presynaptic mAChRs in the inhibition of glutamatergic transmission in the hippocampus. Over the years, however, pharmacological and molecular genetic studies have yielded quite contradictory results regarding the mAChR subtype(s) involved. In this study, multi-electrode array technology was used for the pharmacological elucidation of the subtype of mAChR mediating the depression of excitatory synaptic transmission at the SC-CA1 synapse. Using selective antagonists (VU0255035, MT7, tripinamide, MT3) and allosteric potentiators (VU 10010, VU 0238429) the involvement of M1, M2, M4, and M5 subtypes was ruled out thereby implying a major modulatory role for M3 receptors in the inhibition of excitatory synaptic transmission in area CA1 of rat hippocampus.
2.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.
Bridges TM;Kennedy JP;Cho HP;Breininger ML;Gentry PR;Hopkins CR;Conn PJ;Lindsley CW Bioorg Med Chem Lett. 2010 Jan 15;20(2):558-62. doi: 10.1016/j.bmcl.2009.11.089. Epub 2009 Nov 22.
This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M(5)-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G(q) mAChR M(1), M(3), M(5) PAM. An iterative library synthesis approach delivered the first selective M(5) PAM (no activity at M(1)-M(4) @ 30microM), and an important tool compound to study the role of M(5) in the CNS.
3.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.
Bridges TM;Marlo JE;Niswender CM;Jones CK;Jadhav SB;Gentry PR;Plumley HC;Weaver CD;Conn PJ;Lindsley CW J Med Chem. 2009 Jun 11;52(11):3445-8. doi: 10.1021/jm900286j.
This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). 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.
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CAS 1160247-92-6 VU 0238429

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