Flavan-3-ol derivatives are positive modulators of GABAA receptors with higher efficacy for the α2 subtype and anxiolytic action in mice

Recent genetic and pharmacological studies have demonstrated that alpha(2)-containing GABA(A) receptors mediate the anxiolytic effects of benzodiazepines, setting a new strategy in developing novel, non-sedative anxiolytic agents. In this study we show that stereoisomers of 3-acetoxy-4'-methoxyflavan are positive modulators of recombinant alpha(1,2,3,5)beta(2)gamma(2L) and alpha(1)beta(2) GABA(A) receptors expressed in Xenopus laevis oocytes. GABA(C) receptors are insensitive to modulation by these compounds. In each case, the enhancement was evident at low micromolar concentrations and occurred independently of the classical high affinity benzodiazepine site, as it could not be blocked by the antagonist flumazenil. Importantly, the compound Fa131 was significantly more efficacious at enhancing GABA-induced currents (EC5) at alpha(2)beta(2)gamma(2L) receptors compared to alpha(1)beta(2)gamma(2L), alpha(3)beta(2)gamma(2L) and alpha(5)beta(2)gamma(2L) receptors (E-max = 21.0 +/- 1.7 times, compared to 8.5 +/- 0.7 times at alpha(1)-, 9.5 +/- 0.6 times at alpha(3)- and 5.2 +/- 0.4 times at alpha(5)-contaning GABA(A) receptors), suggesting a potential use as an anxiolytic. In mice, this agent (1-30 mg/kg i.p.) induced anxiolytic-like action in two unconditioned models of anxiety: the elevated plus maze and the light/dark paradigms. No sedative or myorelaxant effects were detected using the hole board, actimeter and horizontal wire tests, and only weak barbiturate-potentiating effects on the loss of righting reflex test. Fa131 demonstrated improved segregation of anxiolytic and sedative doses when compared to the non-selective agonist diazepam. Finally, flavan derivatives highlight the potential of targeting non-benzodiazepine allosteric sites in the search for new anxioselective drugs. (C) 2008 Elsevier Ltd. All rights reserved.