(+)-Hydrastine, a potent competitive antagonist at mammalian GABAA receptors.
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 microM) was 8 times more potent than bicuculline (IC50 19.7 microM). 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 microM) was more potent than bicuculline (IC50 2.3 microM). 6. (+)-Hydrastine, 10 nM to 1 mM, did not inhibit the binding of [3H]-(-)-baclofen to GABAB binding sites in rat brain membranes.
Huang
J H
JH
Department of Pharmacology, University of Sydney, NSW, Australia.
Johnston
G A
GA
D000109:Acetylcholine / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D044182:Benzylisoquinolines; D001640:Bicuculline / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D003292:Convulsants; D003975:Diazepam / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009118:Muscimol / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*; D013237:Stereoisomerism
D000470:Alkaloids; D044182:Benzylisoquinolines; D003292:Convulsants; D011963:Receptors, GABA-A; C052329:phaclofen; D009118:Muscimol; C013024:hydrastine; D001418:Baclofen; D000109:Acetylcholine; D003975:Diazepam; D001640:Bicuculline