When synaptic glutamate is in excess, activation of metabotropic glutamate receptor mGluR3 will decrease glutamate release due to its presynaptic localization in neurons, while increasing glutamate reuptake via transporters due to its expression on glial cells. mGluR3 activation can also increase production of neurotrophic factors (GDNF, BDNF, TGFb) and reduce neuroinflammation. mGluR3 potentiation with positive allosteric modulators (PAMs) has therefore the potential to alleviate symptoms but also delay progression of neurodegenerative disorders such as Parkinson’s or Huntington’s disease, by combination of these anti-excitotoxic, pro-neurotrophic, and anti-inflammatory activities.
We discovered 2 chemical series of mGluR3 PAMs with well-defined SAR, 2-digit nanomolar on-target potency, good selectivity profile, excellent oral bioavailability and BBB penetration. The 2nd series is fully selective against close subtype mGluR2. PoC data were obtained with lead compounds for in vitro neuroprotection, in vitro and in vivo production of neurotrophic factors, and alleviation of motor symptoms in Haldol-induced catalepsy mouse model.
This program is currently at hit-to-lead stage.