(+)-Hydrastine, a potent competitive antagonist at mammalian GABAA receptors

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Abstract
1 (+)-Hydrastine is a phthalide isoquinoline alkaloid, isolated from Corydalis stricta. It has the same 1S,9R configuration as the competitive GABAA receptor antagonist bicuculline and is the enantiomer of the commercially available (−)-hydrastine. 2 (+)-Hydrastine (CD50 0.16 mg kg−1, i.v.) was twice as potent as bicuculline (CD50 0.32 mg kg−1, i.v.) as a convulsant in mice. This action was stereoselective in that (+)-hydrastine was 180 times as potent as (−)-hydrastine. 3 (+)-Hydrastine was a selective antagonist at bicuculline-sensitive GABAA receptors in the guinea-pig isolated ileum. It did not influence phaclofen-sensitive GABAB receptors or acetylcholine receptors in this tissue. (+)-Hydrastine was a competitive antagonist of GABAA responses (pA2 6.5) more potent than bicuculline (pA2 6.1). 4 When tested against the binding of [3H]-muscimol to high affinity GABAA binding sites in rat brain membranes, (+)-hydrastine (IC50 2.37 μm) was 8 times more potent than bicuculline (IC50 19.7 μm). 5 As an antagonist of the activation of low affinity GABAA receptors as measured by the stimulation by GABA of [3H]-diazepam binding to rat brain membranes, (+)-hydrastine (IC50 0.4 μm) was more potent than bicuculline (IC50 2.3 μm). 6 (+)-Hydrastine, 10 nm to 1 mm, did not inhibit the binding of [3H]-(−)-baclofen to GABAB binding sites in rat brain membranes.