Discovery of a novel metabotropic glutamate receptor 4 (mGlu₄) positive allosteric modulator (PAM) extended probe: Characterization of ML292, a potent and selective mGlu₄ PAM which produces efficacy alone or in combination with L-DOPA in preclinical rodent models of Parkinson's disease

ML292 was identified through a medicinal chemistry campaign that was designed to improve the in vivo characteristics of ML128 and ML182. ML292 is a potent and novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGlu₄) – hEC₅₀ = 1196 nM; rEC₅₀ = 330 nM. ML292 shows moderate in vitro and in vivo PK characteristics; however, ML292 was shown to be active in multiple anti-Parkinsonian animal models after systemic dosing. ML292 was superior to ML128 and ML182 in reversing haloperidol-induced catalepsy utilizing a 1.5 mg/kg dose of haloperidol. In addition, ML292 was efficacious alone or when administered in combination with L-DOPA in reversing forelimb asymmetry-induced by unilateral 6-OHDA lesions in rats. The findings that the effects of ML292 to reverse forelimb asymmetry when co-dosed with an inactive dose of L-DOPA suggests that ML292 (and other mGlu₄ PAMs) may be beneficial in L-DOPA sparing activities. ML292 will find utility in the Parkinson’s and mGlu community as a novel, selective and potent PAM of mGlu₄.