Home
Resources
Publications
The Discovery and Characterization of a Centrally Penetrant (ML396) and a Peripherally Restricted (ML397) pan-Group III mGlu Positive Allosteric Modulators

The Discovery and Characterization of a Centrally Penetrant (ML396) and a Peripherally Restricted (ML397) pan-Group III mGlu Positive Allosteric Modulators

Nidhi Jalan-Sakrikar, Julie Roper-Field, Rebecca Klar, Margrith Mattman, Adam G. Walker, Rocio Zamorano, Zixiu Xiang, C. Frank Byers, Anna L. Blobaum, Darren Engers, C. David Weaver, Emily Days, Thomas J. Utley, etc.

PMID: 25834902

Abstract:

Herein we report the discovery and characterization of two, structurally distinct, positive allosteric modulators (PAM) of the Group III metabotropic glutamate receptors (mGlus). The first probe molecule (ML397) was discovered after a high-throughput screening campaign of the original Molecular Libraries Small Molecule Repository (MLSMR) library. ML397 is equipotent as a PAM against mGlu7, mGlu8 and mGlu4 and is selective against Group I and Group II mGlu receptors as well as against the EuroFins Lead Profiling Screen. This probe is unique in that it is peripherally restricted, which allows for distinction from other PAMs or agonists of the Group III mGlus. The second probe molecule (ML396) was discovered after a screen of Vanderbilt's Center for Neuroscience Drug Discovery mGlu4-biased library and is related to a previous ML probe for mGlu4, ML128. ML396 is more potent (∼100 nM against mGlu7, mGlu8 and mGlu4) and displays good brain penetration. By virtue of possessing activity at all group III receptors but not groups I and II, we will be able to use these tools to identify common allosteric binding sites among these receptors which are important targets for drug discovery. Additionally, by capitalizing on a synapse in the hippocampus that exclusively expresses mGlu7, we have validated that each of these probes potentiate agonist responses in a native tissue preparation.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1630936956	ML396		1630936-95-6	Price

As a specialist in analytical chemical Products, Alfa Chemistry offers consumers a wealth of raw materials and a full range of technologies and services.

QUICK LINKS

HEADQUARTERS

Tel:

Fax:

Email: