title: NS11394 [3'-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a unique subtype-selective GABAA receptor positive allosteric modulator: in vitro actions, pharmacokinetic properties and in vivo anxiolytic efficacy.
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 GABA(A) receptors of alpha(5) > alpha(3) > alpha(2) > alpha(1) based on oocyte electrophysiology with human GABA(A) receptors. Compared with other subtype-selective ligands, NS11394 is unique in having superior efficacy at GABA(A)-alpha(3) receptors while maintaining low efficacy at GABA(A)-alpha(1) 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 GABA(A)-alpha(3) receptors, although a contributory role of GABA(A)-alpha(2) 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 GABA(A)-alpha(1) 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 GABA(A)-alpha(5) 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 GABA(A) receptor profile and represents an excellent pharmacological tool to further our understanding on the relative contributions of GABA(A) receptor subtypes in various therapeutic areas.
authors.affiliation: Department of Pharmacology, NeuroSearch A/S, Ballerup, Denmark. max@neurosearch.dk
authors.forename: N R
authors.initials: NR
authors.lastname: Mirza
authors.forename: J S
authors.initials: JS
authors.lastname: Larsen
authors.forename: C
authors.initials: C
authors.lastname: Mathiasen
authors.forename: T A
authors.initials: TA
authors.lastname: Jacobsen
authors.forename: G
authors.initials: G
authors.lastname: Munro
authors.forename: H K
authors.initials: HK
authors.lastname: Erichsen
authors.forename: A N
authors.initials: AN
authors.lastname: Nielsen
authors.forename: K B
authors.initials: KB
authors.lastname: Troelsen
authors.forename: E Ø
authors.initials: EØ
authors.lastname: Nielsen
authors.forename: P K
authors.initials: PK
authors.lastname: Ahring
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D014151:Anti-Anxiety Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy; D001562:Benzimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006801:Humans; D008024:Ligands; D008568:Memory / Q000187:drug effects; D051379:Mice; D010599:Pharmacokinetics; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*
chemical_list: C533864:3'-(5-(1-hydroxy-1-methylethyl)benzoimidazol-1-yl)biphenyl-2-carbonitrile; D014151:Anti-Anxiety Agents; D001562:Benzimidazoles; D058785:GABA-A Receptor Agonists; D008024:Ligands; D011963:Receptors, GABA-A