Chemical Biology of mGlu4 Receptor Activation: Dogmas, Challenges, Strategies and Opportunities

Title:Chemical Biology of mGlu4 Receptor Activation: Dogmas, Challenges, Strategies and Opportunities

Volume: 14 Issue: 15

Author(s): Xinyan Huang, Elena Dale, Robbin M. Brodbeck and Dario Doller

Affiliation:

Keywords: Allosteric ligand, heterodimer, mGlu4 receptor, orthosteric ligand, positive allosteric modulator.

Abstract: Drug design necessitates a clear understanding of the phenotypic response to be elicited by a given ligandtarget interaction. This relationship is relatively well understood for classical biological targets of drug action, but for some novel targets, notably those amenable to allosteric modulation, developing such understanding may represent a more challenging task. In order to gain knowledge on the nature of the functional response derived from mGlu4 receptor activation, its molecular and cell biology are reviewed, including signalling pathways involved, receptor localization in central nervous system and beyond, and potential genetic links to disease. Broadly held views for both, orthosteric agonists as well as allosteric modulators, are compared with specific observations for the case of mGlu4 receptor activation via orthosteric and allosteric mechanisms. First, sub-type selectivity and brain penetration of amino acid mGlu4 receptor agonists are discussed, followed by the quantification of functional allosteric effects, the potential role of heterodimers in the functional response, and the observation of supra-physiological efficacy of mGlu4 receptor PAMs. We show that, in our analysis, these attributes differ from those that may be expected by extrapolating from broad knowledge. In addition, recent progress with mGlu4 receptor radioligands and PET ligands is summarized.

Cite this article as:

Huang Xinyan, Dale Elena, Brodbeck M. Robbin and Doller Dario, Chemical Biology of mGlu4 Receptor Activation: Dogmas, Challenges, Strategies and Opportunities, Current Topics in Medicinal Chemistry 2014; 14 (15) . https://dx.doi.org/10.2174/1568026614666140902143830