Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites

A group III metabotropic glutamate
(mGlu) receptor agonist (PCEP)
was identified by virtual HTS. This orthosteric ligand is composed
by an l-AP4-derived fragment that mimics glutamate and a
chain that binds into a neighboring pocket, offering possibilities
to improve affinity and selectivity. Herein we describe a series of
derivatives where the distal chain is replaced by an aromatic or heteroaromatic
group. Potent agonists were identified, including some with a mGlu4 subtype preference, e.g., 17m (LSP1-2111) and 16g (LSP4-2022). Molecular modeling suggests that aromatic
functional groups may bind at either one of the two chloride regulatory
sites. These agonists may thus be considered as particular bitopic/dualsteric
ligands. 17m was shown to reduce GABAergic synaptic transmission
at striatopallidal synapses. We now demonstrate its inhibitory effect
at glutamatergic parallel fiber–Purkinje cell synapses in the
cerebellar cortex. Although these ligands have physicochemical properties
that are markedly different from typical CNS drugs, they hold significant
therapeutic potential.