Abstract
The novel positive allosteric modulator NS11394 [3′-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] possesses a functional selectivity profile at GABAA receptors of α5 > α3 > α2 > α1 based on oocyte electrophysiology with human GABAA receptors. Compared with other subtype-selective ligands, NS11394 is unique in having superior efficacy at GABAA-α3 receptors while maintaining low efficacy at GABAA-α1 receptors. NS11394 has an excellent pharmacokinetic profile, which correlates with pharmacodynamic endpoints (CNS receptor occupancy), yielding a high level of confidence in deriving in vivo conclusions anchored to an in vitro selectivity profile and allowing for translation to higher species. Specifically, we show that NS11394 is potent and highly effective in rodent anxiety models. The anxiolytic efficacy of NS11394 is most probably mediated through its high efficacy at GABAA-α3 receptors, although a contributory role of GABAA-α2 receptors cannot be excluded. Compared with benzodiazepines, NS11394 has a significantly reduced side effect profile in rat (sedation, ataxia, and ethanol interaction) and mouse (sedation), even at full CNS receptor occupancy. We attribute this benign side effect profile to very low efficacy of NS11394 at GABAA-α1 receptors and an overall partial agonist profile across receptor subtypes. However, NS11394 impairs memory in both rats and mice, which is possibly attributable to its efficacy at GABAA-α5 receptors, albeit activity at this receptor might be relevant to its antinociceptive effects (J Pharmacol Exp Ther 327:doi;10.1124/jpet.108.144, 2008). In conclusion, NS11394 has a unique subtype-selective GABAA receptor profile and represents an excellent pharmacological tool to further our understanding on the relative contributions of GABAA receptor subtypes in various therapeutic areas.
Footnotes
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.108.138859.
-
ABBREVIATIONS: L-838,417, 7-tert-butyl-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluoro-phenyl)-1,2,4-triazolo[4,3-b]pyridazine; SL651498, 6-fluoro-9-methyl-2-phenyl-4-(pyrrolidine-1-carbonyl)-2,9-dihydro-beta-carbolin-1-one; TPA023, 7-tert-butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; CNS, central nervous system; GABA, γ-aminobutyric acid; CER, conditioned emotional response; FPT, four-plate testing; L, light; D, dark; VI, variable interval; HEK-293, human embryonic kidney 293; PCR, polymerase chain reaction; Ro 15-788, flumazenil; Ro 15-4513, ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-α]-[1,4]benzodiazepine-3-carboxylate; SR, suppression ratio; h, human; TP003, 4,2′-difluoro-5′-[8-fluoro-7-(1-hydroxy-1-methyl-ethyl)-imidazol[1,2-a]pyridin-3-yl]-biphenyl-2-carbonitrile; NG2-73, 7-[2-(3-fluoropyridin-2-yl)-imidazol-1-ylmethyl]-2-methyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine.
- Received March 7, 2008.
- Accepted July 24, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
