title: Pharmacological characterization of a novel positive modulator at alpha 4 beta 3 delta-containing extrasynaptic GABA(A) receptors.
abstract: The in vitro and in vivo pharmacological effects of [2-amino-4-(2,4,6-trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester (AA29504), which is a close analogue of retigabine, have been investigated. AA29504 induced a rightward shift of the activation threshold at cloned KCNQ2, 2/3 and 4 channels expressed in Xenopus oocytes, with a potency 3-4fold lower than retigabine. AA29504 (1 muM) had no agonist activity when tested at alpha(1)beta(3)gamma(2s) or alpha(4)beta(3)delta GABA(A) receptors expressed in Xenopus oocytes, but left-shifted the EC(50) for GABA and gaboxadol (THIP) at both receptors. The maximum GABA response at alpha(1)beta(3)gamma(2s) receptors was unchanged by AA29504 (1 muM), but increased 3-fold at alpha(4)beta(3)delta receptors. In slices prepared from the prefrontal cortex of adult rats AA29504 had no effect alone on the average IPSC or the tonic current in layer II/III pyramidal neurons, but potentiated the effect of gaboxadol on both phasic and tonic currents. Thus, the effects of gaboxadol could be positively modulated by AA29504. Systemic administration of AA29504 at doses relevant for modulating GABA transmission produced anxiolytic effects and reduced motor coordination consistent with activity at GABA(A) receptors. We conclude that AA29504 exerts a major action via alpha(4)beta(3)delta-containing GABA(A) receptors, which will be important for interpreting its effect in vivo.
authors.affiliation: Discovery Biology Research, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Hoestgaard-Jensen
authors.forename: N O
authors.initials: NO
authors.lastname: Dalby
authors.forename: T D
authors.initials: TD
authors.lastname: Wolinsky
authors.forename: C
authors.initials: C
authors.lastname: Murphey
authors.forename: K A
authors.initials: KA
authors.lastname: Jones
authors.forename: M
authors.initials: M
authors.lastname: Rottländer
authors.forename: K
authors.initials: K
authors.lastname: Frederiksen
authors.forename: W P
authors.initials: WP
authors.lastname: Watson
authors.forename: K
authors.initials: K
authors.lastname: Jensen
authors.forename: B
authors.initials: B
authors.lastname: Ebert
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects / Q000502:physiology / Q000523:psychology; D005260:Female; D018757:GABA Modulators / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020033:Protein Isoforms / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism*; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis
chemical_list: D018757:GABA Modulators; C546260:GABRA4 protein, human; C546273:GABRB3 protein, human; D020033:Protein Isoforms; D021122:Protein Subunits; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid