(+)‐Hydrastine, a potent competitive antagonist at mammalian GABA_A receptors

Abstract

(+)‐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. (+)‐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. (+)‐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). 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). 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). (+)‐Hydrastine, 10 nm to 1 mm, did not inhibit the binding of [3H]‐(−)‐baclofen to GABAB binding sites in rat brain membranes.

Pharmacologic Specificity of Nicotinic Receptor-Mediated Relaxation of Muscarinic Receptor Precontracted Human Gastric Clasp and Sling Muscle Fibers within the Gastroesophageal Junction

“…The potencies of bicuculline and strychnine in clasp, sling, and LEC fibers (Table 1) were much lower than their reported potencies at GABA A (Maggi et al, 1984;Huang and Johnston, 1990) and glycine receptors (Lynch, 2004), respectively, and within their reported potency for antagonism of nicotinic receptors (Zhang and Feltz, 1991;Kuijpers et al, 1994;Albuquerque et al, 1998;Demuro et al, 2001). Therefore, other antagonists with no reported activity at nicotinic receptors were used: the GABA A antagonist SR95531 (Tonini et al, 1989;Zhang and Feltz, 1991) and the glycine receptor antagonist ginkgolide B (Kondratskaya et al, 2002(Kondratskaya et al, , 2004 in six to eight separate clasp and sling muscle strips from two different donors.…”

GABA agonists and antagonists

“…However, (+)-hydrastine [(+)-HYDR], with two methoxy groups replacing the methylenedioxy bridge of the phthalide benzoisofuranone moiety, is even more active than (+)-bicuculline as a GABA,-receptor antagonist, and the most active known phthalide isoquinoline antagonist. 82 Opening the lactone ring of bicuculline to give bicucine (BCC) totally inactivates its antagonist activity. Since the lactone readily opens under unfavourable conditions of pH,83 this property originally contributed to considerable confusion over early attempts to identify synapses where bicuculline-sensitive GABAergic inhibition might operate.…”

Alkaloids

“…421 Paradoxically, the injection of GABA at a dose of 200 mg/kg daily to C57Bl/6J EAE mice immunized with MOG 35-55 fostered both secretion of TNF-α and IL-6 and paralysis. 423 Consequently, these alkaloids are powerful poisons that enforce seizures in rodents with CD 50 values equal to 0.1 mg/kg and 0.3 mg/kg, respectively, 423 and which are not possibly usable in therapeutics. (family Papaveraceae Juss.)…”