Correlation between brain/plasma ratios and efficacy in neuropathic pain models of selective metabotropic glutamate receptor 1 antagonists.
We have discovered a novel, potent, and selective triazafluorenone series of metabotropic glutamate receptor 1 (mGluR1) antagonists with efficacy in various rat pain models. Pharmacokinetic and pharmacodynamic profiles of these triazafluorenone analogs revealed that brain/plasma ratios of these mGluR1 antagonists were important to achieve efficacy in neuropathic pain models. This correlation could be used to guide our in vivo SAR (structure-activity relationship) modification. For example, compound 4a has a brain/plasma ratio of 0.34, demonstrating only moderate efficacy in neuropathic pain models. On the other hand, antagonist 4b with a brain/plasma ratio of 2.70 was fully efficacious in neuropathic pain models.
Zheng
Guo Zhu
GZ
Neuroscience Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6115, USA. gouzhu.zheng@abbott.com
Bhatia
Pramila
P
Kolasa
Teodozyj
T
Patel
Meena
M
El Kouhen
Odile F
OF
Chang
Renjie
R
Uchic
Marie E
ME
Miller
Loan
L
Baker
Scott
S
Lehto
Sonya G
SG
Honore
Prisca
P
Wetter
Jill M
JM
Marsh
Kennan C
KC
Moreland
Robert B
RB
Brioni
Jorge D
JD
Stewart
Andrew O
AO
D000818:Animals; D001372:Aza Compounds / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D023421:Models, Animal; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001372:Aza Compounds; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1