title: Chemical biology of mGlu4 receptor activation: dogmas, challenges, strategies and opportunities.
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.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Huang
authors.forename: Elena
authors.initials: E
authors.lastname: Dale
authors.forename: Robbin M
authors.initials: RM
authors.lastname: Brodbeck
authors.affiliation: Molecular Pharmacology & SAR. Neuroinflammation Disease Biology Unit, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA. xhua@lundbeck.com.
authors.forename: Dario
authors.initials: D
authors.lastname: Doller
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D001692:Biological Transport; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D015195:Drug Design; D005786:Gene Expression Regulation; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055503:Protein Multimerization; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D007473:Ion Channels; D008024:Ligands; D019275:Radiopharmaceuticals; D018094:Receptors, Metabotropic Glutamate; D054852:Small Molecule Libraries; D020928:Mitogen-Activated Protein Kinases; C108823:metabotropic glutamate receptor 4