♦ See referenced article, J. Biol. Chem. 2014, 289, 10975–10987
A receptor in the central nervous system called metabotropic glutamate receptor subtype 7 (mGlu7) has been implicated in a number of neurological disorders such as depression, drug abuse, and autism. There are no suitable molecules that specifically block mGlu7 in critical brain areas involved in emotion. In this Paper of the Week, a team led by Peter Flor at the University of Regensburg in Germany described a molecule called XAP044 that selectively targets mGlu7 in the amygdala of mouse brains. The investigators demonstrated that XAP044 acts on an extracellular domain of the receptor, a mode of action not seen with other mGlu7 drugs. When XAP044 acts on this extracellular domain, it disrupts a G protein signaling pathway in which mGlu7 is involved. The investigators also showed that the molecule works in mice to reduce stress, depressive, and anxiety behaviors. The authors concluded, “We present an mGlu7 antagonist with a novel molecular mode of pharmacological action, providing significant application potential in psychiatry.”
XAP044 selectively antagonizes [35S]GTPγS binding via mGlu7.