Engers Darren W., Jones Carrie K., Bubser Michael, Thompson Analisa D., Blobaum Anna L., Sheffler Douglas J., Zamorano Rocio, Carrington Sheridan J. S., Bridges Thomas M., Morrison Ryan D., Daniels J. Scott, Conn P. Jeffrey, Lindsley Craig W., Niswender Colleen M., Hopkins Corey R.
Vanderbilt Specialized Chemistry Center, Vanderbilt University Medical Center
ML292 was identified through a medicinal chemistry campaign that was designed to improve the characteristics of ML128 and ML182. ML292 is a potent and novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGlu) – hEC = 1196 nM; rEC = 330 nM. ML292 shows moderate and 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 mGlu 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 mGlu.
ML292是通过旨在改善ML128和ML182特性的药物化学研究确定的。ML292是一种强效且新型的代谢型谷氨酸受体4（mGlu）的正变构调节剂（PAM）——人源效力浓度（hEC）=1196 nM；大鼠效力浓度（rEC）=330 nM。ML292显示出适度的药代动力学（PK）特性；然而，全身给药后，ML292在多种抗帕金森病动物模型中表现出活性。在使用1.5 mg/kg剂量氟哌啶醇的情况下，ML292在逆转氟哌啶醇诱导的僵住症方面优于ML128和ML182。此外，ML292单独使用或与左旋多巴联合给药时，均可有效逆转大鼠单侧6-羟基多巴胺（6-OHDA）损伤引起的前肢不对称。ML292与无效剂量的左旋多巴共同给药时可逆转前肢不对称，这一发现表明ML292（以及其他mGlu PAM）可能在左旋多巴节省活性方面具有益处。作为一种新型、选择性且强效的mGlu PAM，ML292将在帕金森病和mGlu研究领域发挥作用。
