VU0483605

Glutamate, the major excitatory neurotransmitter in the CNS, activates eight known subtypes of metabotropic glutamate receptors (mGluRs). Highly selective modulators designed to act at allosteric sites on certain mGluR subtypes are being developed to preferentially regulate subtype-specific, glutamate-induced receptor activation.¹ VU0483605 is a selective positive allosteric modulator (PAM) of mGluR1, displaying EC₅₀ values of 0.39 and 0.36 μM at human and rat receptors, respectively, and no activity as a mGlu4 PAM (EC₅₀ >10 μM).² It has been shown to potentiate a response to glutamate in wild-type cell lines stably expressing mGlu1 and to partially restore the reduction in glutamate-mediated calcium signaling in a mutant cell model of schizophrenia.²

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1. Sheffler, D.J., and Conn, P.J. Allosteric potentiators of metabotropic glutamate receptor subtype 1a differentially modulate independent signaling pathways in baby hamster kidney cells. Neuropharmacology 55(4), 419-427 (2008).

2. Cho, H.P., Garcia-Barrantes, P.M., Brogan, J.T., et al. Chemical modulation of mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenics. ACS Chem. Biol. 9(10), 2234-2246 (2014).