title: Correlation between brain/plasma ratios and efficacy in neuropathic pain models of selective metabotropic glutamate receptor 1 antagonists.
abstract: 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.
authors.affiliation: Neuroscience Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6115, USA. gouzhu.zheng@abbott.com
authors.forename: Guo Zhu
authors.initials: GZ
authors.lastname: Zheng
authors.forename: Pramila
authors.initials: P
authors.lastname: Bhatia
authors.forename: Teodozyj
authors.initials: T
authors.lastname: Kolasa
authors.forename: Meena
authors.initials: M
authors.lastname: Patel
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: Scott
authors.initials: S
authors.lastname: Baker
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Lehto
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Jill M
authors.initials: JM
authors.lastname: Wetter
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
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: 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
chemical_list: D001372:Aza Compounds; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1