Structure-activity relationship of triazafluorenone derivatives as potent and selective mGluR1 antagonists.
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.
Zheng
Guo Zhu
GZ
Neuroscience Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6115, USA. Guozhu.zheng@Abbott.com
Bhatia
Pramila
P
Daanen
Jerome
J
Kolasa
Teodozyj
T
Patel
Meena
M
Latshaw
Steven
S
El Kouhen
Odile F
OF
Chang
Renjie
R
Uchic
Marie E
ME
Miller
Loan
L
Nakane
Masaki
M
Lehto
Sonya G
SG
Honore
Marie P
MP
Moreland
Robert B
RB
Brioni
Jorge D
JD
Stewart
Andrew O
AO
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
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