title: Structure-activity relationship of triazafluorenone derivatives as potent and selective mGluR1 antagonists.
abstract: SAR (structure-activity relationship) studies of triazafluorenone derivatives as potent mGluR1 antagonists are described. The triazafluorenone derivatives are non-amino acid derivatives and noncompetitive mGluR1 antagonists that bind at a putative allosteric recognition site located within the seven-transmembrane domain of the receptor. These triazafluorenone derivatives are potent, selective, and systemically active mGluR1 antagonists. Compound 1n, for example, was a very potent mGluR1 antagonist (IC50 = 3 nM) and demonstrated full efficacy in various in vivo animal pain models.
authors.affiliation: Neuroscience Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6115, USA. Guozhu.zheng@Abbott.com
authors.forename: Guo Zhu
authors.initials: GZ
authors.lastname: Zheng
authors.forename: Pramila
authors.initials: P
authors.lastname: Bhatia
authors.forename: Jerome
authors.initials: J
authors.lastname: Daanen
authors.forename: Teodozyj
authors.initials: T
authors.lastname: Kolasa
authors.forename: Meena
authors.initials: M
authors.lastname: Patel
authors.forename: Steven
authors.initials: S
authors.lastname: Latshaw
authors.forename: Odile F
authors.initials: OF
authors.lastname: El Kouhen
authors.forename: Renjie
authors.initials: R
authors.lastname: Chang
authors.forename: Marie E
authors.initials: ME
authors.lastname: Uchic
authors.forename: Loan
authors.initials: L
authors.lastname: Miller
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakane
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Lehto
authors.forename: Marie P
authors.initials: MP
authors.lastname: Honore
authors.forename: Robert B
authors.initials: RB
authors.lastname: Moreland
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Stewart
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002531:Cerebellum / Q000378:metabolism; D005449:Fluorenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D010147:Pain Measurement; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C507031:9-dimethylamino-3-(4-ethylphenyl)-3H-5-thia-1,3,6-triazafluoren-4-one; D000700:Analgesics; D001372:Aza Compounds; D005449:Fluorenes; D006575:Heterocyclic Compounds, 3-Ring; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D002118:Calcium