title: Selective Negative Allosteric Modulation Of Metabotropic Glutamate Receptors – A Structural Perspective of Ligands and Mutants.
abstract: The metabotropic glutamate receptors have a wide range of modulatory functions in the central nervous system. They are among the most highly pursued drug targets, with relevance for several neurological diseases, and a number of allosteric modulators have entered clinical trials. However, so far this has not led to a marketed drug, largely because of the difficulties in achieving subtype-selective compounds with desired properties. Very recently the first crystal structures were published for the transmembrane domain of two metabotropic glutamate receptors in complex with negative allosteric modulators. In this analysis, we make the first comprehensive structural comparison of all metabotropic glutamate receptors, placing selective negative allosteric modulators and critical mutants into the detailed context of the receptor binding sites. A better understanding of how the different mGlu allosteric modulator binding modes relates to selective pharmacological actions will be very valuable for rational design of safer drugs.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Harpsøe
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Vignir
authors.initials: V
authors.lastname: Isberg
authors.affiliation: Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, UK.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Tehan
authors.affiliation: Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, UK.
authors.forename: Dahlia
authors.initials: D
authors.lastname: Weiss
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Angela
authors.initials: A
authors.lastname: Arsova
authors.affiliation: Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, UK.
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Marshall
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: David E
authors.initials: DE
authors.lastname: Gloriam
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D011485:Protein Binding; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D018094:Receptors, Metabotropic Glutamate