The metabotropic glutamate receptor 4 (mGlu4) belongs to the Group III mGlu receptors (Class C G Protein-Coupled Receptors) and is negatively coupled to adenylate cyclase via activation of the Gαi/o protein. It is expressed primarily on presynaptic terminals, functioning as an autoreceptor or heteroceptor and its activation thus leading to decreases in glutamate and GABA transmitter release into the synapse.
mGlu4 PAM is emerging as a promising target for the treatment of motor (and non-motor) symptoms in Parkinson’s disease through a non-dopaminergic approach, as well as offering a potential for disease-modification.
Addex has identified several new series of compounds acting as mGlu4 positive allosteric modulators with nanomolar potency, highly selective versus all other mGlu receptor subtypes, and achieving brain penetration compatible with a treatment for CNS disorders. The program is in late stage lead optimisation.
ADX88178 has been published as pharmacological tool to explore the potential of the mGlu4 PAM approach, but also to better understand the function of this receptor (see Publications section).