title: Discovery, synthesis, and structure-activity relationships of 2-aminoquinazoline derivatives as a novel class of metabotropic glutamate receptor 5 negative allosteric modulators.
abstract: A virtual screening approach using various in silico methodologies led to the discovery of 2-(m-tolylamino)-7,8-dihydroquinazolin-5(6H)-one (1) as a moderately active negative allosteric modulator (NAM) of the metabotropic glutamate receptor subtype 5 (mGluR5) showing high selectivity against the subtype mGluR1. Modifications of the parent compound by rational design yielded a series of highly potent derivatives which will serve as valuable starting points for further hit-to-lead optimization efforts toward a suitable drug candidate for the treatment of L-DOPA induced dyskinesia.
authors.affiliation: Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318 Frankfurt am Main, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Kubas
authors.forename: Udo
authors.initials: U
authors.lastname: Meyer
authors.forename: Bjoern
authors.initials: B
authors.lastname: Krueger
authors.forename: Mirko
authors.initials: M
authors.lastname: Hechenberger
authors.forename: Maksims
authors.initials: M
authors.lastname: Vanejevs
authors.forename: Ronalds
authors.initials: R
authors.lastname: Zemribo
authors.forename: Valerjans
authors.initials: V
authors.lastname: Kauss
authors.forename: Raisa
authors.initials: R
authors.lastname: Ambartsumova
authors.forename: Ilya
authors.initials: I
authors.lastname: Pyatkin
authors.forename: Alexey I
authors.initials: AI
authors.lastname: Polosukhin
authors.forename: Ulrich
authors.initials: U
authors.lastname: Abel
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D002478:Cells, Cultured; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D052999:Quinazolinones / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists; D013329:Structure-Activity Relationship; D014052:Toluidines / Q000737:chemistry* / Q000494:pharmacology*; D014584:User-Computer Interface
chemical_list: C585973:2-(m-tolylamino)-7,8-dihydroquinazolin-5(6H)-one; C573775:4-aminoquinazoline; D011799:Quinazolines; D052999:Quinazolinones; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D014052:Toluidines; C104077:metabotropic glutamate receptor type 1
keywords: Allosteric modulator; Metabotropic glutamate receptor; Virtual screening; l-DOPA induced dyskinesia; mGluR5