GABAA receptor modulator
AA 29504, {2-amino-4-(2, 4, 6-trimethylbenzylamino)-phenyl}-carbamic acid ethyl ester is a positive modulator of extrasynaptic GABAA receptors. AA 29504 is also an analogue of the KCNQ channel opener retigabine with a 3-4 fold lower potency than retigabine. The EC50 of AA 29504 at KCNQ channels is between 9.6 and 13.5 μM [2]. AA 29504 at 1 μM had no agonist activity when tested at α1β3γ2s or α4β3δ GABAA receptors expressed in Xenopus oocytes, but left-shifted the EC50 of GABA and gaboxadol (THIP) at both receptors. The maximum GABA response was unchanged at α1β3γ2s receptors by AA 29504 (1 μM), but increased 3-fold at α4β3δ receptors [1].
GABA transiently activates synaptic GABAA receptors, leading to the classical inhibitory post-synaptic currents (phasic inhibition) [2]. KCNQ (also termed Kv7) channels are voltage-dependent potassium channels composed of homo- and heteromeric complexes of five different KCNQ subunits (KCNQ1–5, or called Kv7.1–Kv7.5) [3].
In Xenopus oocytes, AA 29504 at concentrations below 3 μM exhibited no intrinsic activity, whereas at 3 μM and above AA 29504 could induce a small response, which could not be blocked by bicuculline. Treatment with AA 29504 at a concentration of 1 μM showed no intrinsic activity at GABAA receptors and KCNQ channels, but left-shifted the concentration-response curve of GABA without affecting the maximum response to GABA [1].
In sub-chronic phencyclidine (PCP)-treated rats, acute administration of AA 29504 at 1 and 4 mg/kg reversed the PCP-induced deficit, but the middle dose of 2 mg/kg did not. Treatment with AA 29504 did not affect locomotor activity. AA 29504-treated animal groups were unable to significantly discriminate the novel objects from the familiar objects. The group treated with AA 29504 at 2 mg/kg showed a small but significant preference for the left object [2].
参考文献:
[1].? K. Hoestgaard-Jensen, N.O. Dalby, T.D. Wolinsky, et al. Pharmacological characterization of a novel positive modulator at α4β3δ-containing extrasynaptic GABAA receptors. Neuropharmacology, 2010, 58:702-711.
[2].? Trine Damgaard, Niels Plath, Jo C. Neill, et al. Extrasynaptic GABAA receptor activation reverses recognition memory deficits in an animal model of schizophrenia. Psychopharmacology, 2011, 214:403-413.
[3].? Henrik H. Hansen, Christina Ebbesen, Claus Mathiesen, et al. The KCNQ Channel Opener Retigabine Inhibits the Activity of Mesencephalic Dopaminergic Systems of the Rat. Journal of Pharmacology and Experimental Therapeutics, 2006, 318(3): 1006–1019.
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