Allosteric modulation of mGluR1-8 has been shown to offer an attractive strategy to develop oral small molecule therapeutics that can be administered orally and that readily cross the blood-brain barrier. Allosteric modulators of both mGluR5 and mGluR4 are emerging as a novel and highly desirable approaches to the treatment of Parkinson 's disease. mGluR5 negative allosteric modulation (NAM) is a clinically proven mechanism for Parkinson's disease levodopa-induced dyskinesia (PD-LID). The discovery, pharmacological profiling and preclinical validation of dipraglurant will be presented. mGluR4 positive allosteric modulation (PAM) has been extensively characterized as a valuable mechanism for motor and non-motor symptoms improvement in PD. The identification and drug discovery efforts of novel mGluR4 PAM chemotypes towards proof of concept in relevant preclinical models of PD will be described. Profiling of ADX88178, the first nanomolar, selective, brain penetrant and orally active mGluR4 PAM will be discussed.

Progress on allosteric modulation of mGluR5 and mGluR4: Towards new treatment paradigms in Parkinson's disease

244th National Meeting (2012)

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