mGluR (metabotropic glutamate receptor) is a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs act through binding glutamate (L-glutamic acid), the major excitatory transmitter in the mammalian central nervous system (CNS). Furthermore, the mGluRs perform a variety of functions in the central and peripheral nervous systems: mGluRs are involved in learning, memory, anxiety, and the perception of pain.

Among them, mGlu5 is an excitatory Gq-coupled GPCRs predominantly expressed on the postsynaptic sites of neurons.

In addition to the orthosteric site (the site where the endogenous ligand glutamate binds), at least two distinct allosteric binding sites exist on the mGluR5. Selective antagonists and negative allosteric modulators of mGluR5 are a particular area of interest for pharmaceutical research, due to their demonstrated anxiolytic, antidepressant, and anti-addictive effects in animal studies and their relatively benign safety profile.

VU0409106 is a potent, selective, and brain-penetrant mGlu5 negative allosteric modulator (NAM). Meanwhile, VU0409106 shows selection for mGlu5 over other groups I, II and III mGlu receptor subtypes and a panel of GPCRs, ion channels, kinases, and transporters. In addition, VU0409106 demonstrates good CNS exposure following intraperitoneal dosing in mice. This compound behaves with high clearance and short half-life. Gratifyingly, VU0409106 displays anxiolytic effects in a concentration-dependent manner in a mouse marble burying model of anxiety. Moreover, VU0409106 produces concentration-dependent anxiolytic effects in multiple rat models.  Besides, VU0409106 has a significant species difference in the biotransformation of the compound across Sprague-Dawley rat, beagle dog, cynomolgus monkey, and human.

In conclusion, VU0409106 is a potent, selective and brain-penetrant mGlu5 negative allosteric modulator with anxiolytic effects.


[1] Ryan D Morrison, et al. Drug Metab Dispos. 2012 Sep;40(9):1834-45.

[2] Andrew S Felts, et al. Bioorg Med Chem Lett. 2013 Nov 1;23(21):5779-85.