title: An inverse agonist selective for alpha5 subunit-containing GABAA receptors enhances cognition.
abstract: Alpha5IA is a compound that binds with equivalent subnanomolar affinity to the benzodiazepine (BZ) site of GABA(A) receptors containing an alpha1, alpha2, alpha3, or alpha5 subunit but has inverse agonist efficacy selective for the alpha5 subtype. As a consequence, the in vitro and in vivo effects of this compound are mediated primarily via GABA(A) receptors containing an alpha5 subunit. In a mouse hippocampal slice model, alpha5IA significantly enhanced the burst-induced long-term potentiation of the excitatory postsynaptic potential in the CA1 region but did not cause an increase in the paroxysmal burst discharges that are characteristic of convulsant and proconvulsant drugs. These in vitro data suggesting that alpha5IA may enhance cognition without being proconvulsant were confirmed in in vivo rodent models. Hence, alpha5IA significantly enhanced performance in a rat hippocampal-dependent test of learning and memory, the delayed-matching-to-position version of the Morris water maze, with a minimum effective oral dose of 0.3 mg/kg, which corresponded to a BZ site occupancy of 25%. However, in mice alpha5IA was not convulsant in its own right nor did it potentiate the effects of pentylenetetrazole acutely or produce kindling upon chronic dosing even at doses producing greater than 90% occupancy. Finally, alpha5IA was not anxiogenic-like in the rat elevated plus maze nor did it impair performance in the mouse rotarod assay. Together, these data suggest that the GABA(A) alpha5-subtype provides a novel target for the development of selective inverse agonists with utility in the treatment of disorders associated with a cognitive deficit.
authors.affiliation: Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Rd., Harlow, Essex CM20 2QR, UK.
authors.forename: G R
authors.initials: GR
authors.lastname: Dawson
authors.forename: K A
authors.initials: KA
authors.lastname: Maubach
authors.forename: N
authors.initials: N
authors.lastname: Collinson
authors.forename: M
authors.initials: M
authors.lastname: Cobain
authors.forename: B J
authors.initials: BJ
authors.lastname: Everitt
authors.forename: A M
authors.initials: AM
authors.lastname: MacLeod
authors.forename: H I
authors.initials: HI
authors.lastname: Choudhury
authors.forename: L M
authors.initials: LM
authors.lastname: McDonald
authors.forename: G
authors.initials: G
authors.lastname: Pillai
authors.forename: W
authors.initials: W
authors.lastname: Rycroft
authors.forename: A J
authors.initials: AJ
authors.lastname: Smith
authors.forename: F
authors.initials: F
authors.lastname: Sternfeld
authors.forename: F D
authors.initials: FD
authors.lastname: Tattersall
authors.forename: K A
authors.initials: KA
authors.lastname: Wafford
authors.forename: D S
authors.initials: DS
authors.lastname: Reynolds
authors.forename: G R
authors.initials: GR
authors.lastname: Seabrook
authors.forename: J R
authors.initials: JR
authors.lastname: Atack
mesh_terms: D000818:Animals; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007696:Kindling, Neurologic / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; C496250:Gabra5 protein, mouse; D011963:Receptors, GABA-A