Allosteric modulation of the metabotropic glutamate receptors is a field receiving significant focus, both in basic science and in drug development. Nevertheless, there is a notable absence of suitable, potent NAM tool compounds for the Group III mGlus 4,6 and 8. [1] A number of recent publications have highlighted the need for selective mGlu4 NAMs as pharmacological tools to help elucidate the biology and probe therapeutic implications of this receptor. [2a, 2b, 3] The only two published mGlu4 NAMs - a small molecule [3] and a photoswitchable tool compound [4] suffer from low potency (5-10 uM). Our efforts towards the identification of mGlu4 negative allosteric modulators as tool compounds suitable for investigation of mGlu4 biology will be presented.

[1] Branden J. Stansley and P. Jeffrey Conn, Trends in Pharmacological Sciences, 2019, 40, 240-252.
[2a] Kasper Harpsøe, Vignir Isberg, Benjamin G. Tehan, Dahlia Weiss, Angela Arsova, Fiona H. Marshall, Hans Bräuner-Osborne & David E. Gloriam, Scientific Reports, 2015, 5, 13869.
[2b] Chaki, Shigeyuki, Hiroyuki Koike, and Kenichi Fukumoto, Chronic Stress, 2019, doi:10.1177/2470547019837712.
[3] Thomas Utley, Dustin Haddenham, James M. Salovich, Rocio Zamorano, Paige N. Vinson, Craig W. Lindsley, Corey R. Hopkins and Colleen M. Niswender, Bioorganic & Medicinal Chemistry Letters, 2011, 21, 6955-6959.
[4] Xavier Rovira, Ana Trapero, Silvia Pittolo, Charleine Zussy, Adele Faucherre, Chris Jopling, Jesud Giraldo, Jean-Philippe Pin, Pau Gorostiza, Cyril Goudet and Amadeu Llebaria, Cell Chemical Biology, 2016, 23, 929-934.