Recent advances in the drug discovery of metabotropic glutamate receptor 4 (mGluR4) activators for the treatment of CNS and non-CNS disorders

Abstract

Introduction: The metabotropic glutamate receptor type 4 (mGluR4) plays a pivotal role in a plethora of therapeutic areas, as recently demonstrated in preclinical validation studies with several chemical classes of compounds in rodent models of central nervous system (CNS) and peripheral disorders. Activation of mGluR4 with orthosteric agonists, allosteric agonists or pure positive allosteric modulators (PAM) has been postulated to be of broad therapeutic use.

Areas covered: The authors address past and current drug discovery efforts, insights and achievements in the field toward the identification of therapeutically promising and emerging class of mGluR4 activators, over the 2005 – 2011 period. Chemical structures, properties and in vivo pharmacological results discussed in the present review were retrieved from public literature including PubMed searches, Thomson Pharma and SciFinder databases searches, conferences, proceedings and posters.

Expert opinion: Developing a subtype-selective, orally bioavailable brain penetrant mGluR4 orthosteric agonist remains challenging. Lack of subtype selectivity and low brain penetration has been a common limitation of the first generation of mGluR4 agonist and potentiators. However, significant progress has recently been made with the identification of several double- to single-digit nanomolar mGluR4 PAM having reasonable pharmacokinetic properties, oral bioavailability and brain penetration. The use of such compounds in research has led to advancement in understanding the central role of mGluR4 in multiple neurodegenerative and neuroinflammatory disorders, such as Parkinson's disease and multiple sclerosis. Our understanding of the potential application of mGluR4 as therapeutic target is expected to grow as these compounds advance into preclinical and clinical development.

Keywords::

• ADX88178
• central nervous system
• class C GPCRs
• glutamate
• l-DOPA
• LSP4-2022
• metabotropic glutamate receptor 4
• neuroinflammation
• orthosteric agonist
• Parkinson's disease
• PHCCC
• positive allosteric modulator
• potentiator
• preladenant
• VU0364770

Acknowledgements

The authors thank the reviewers of this manuscript for their suggestions, and colleagues from Addex Pharmaceuticals: S Poli, J-P Rocher, R Lutjens, M Kalinichev and B Perry for their time in peer-reviewing this manuscript.

Notes

This box summarizes key points contained in the article.