(+)-Hydrastine, a potent competitive antagonist at mammalian GABAA receptors (original) (raw)
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Securinine alkaloids: A new class of GABA receptor antagonist
Brain Research, 1985
Experiments were undertaken to determine the site of action of securinine and related convulsant indolizidines. All of these compounds induced tonic seizures in mice, with CD50 values ranging from 11 to 87 mg/kg. The CDs0 for bicuculline was found to be 8 mg/kg. Equilibrium binding assays revealed that securinine and dihydrosecurinine inhibit [3H]GABA binding to rat brain membranes with an IC50 of approximately 50 aM, which is some 7 times less potent than bicuculline. Allosecurinine and virosecurinine have IC50 values greater than 1 mM. Both dihydrosecurinine and securinine inhibited GABA-stimulated benzodiazepine binding in rat brain membranes, though they were somewhat weaker than bicuculline in this respect. Other binding assays revealed that securinine and its analogs were inactive as inhibitors of bicuculline-insensitive GABA binding, benzodiazepine, cholinergic muscarinic, and fl-adrenergic receptor binding. In addition, while thiocyanate ion increased the apparent binding potency of bicucuiline 10-fold, it had little effect on that of securinine. Extracellular electrophysiological studies on neurons in the cat spinal cord indi6ated that securinine and dihydrosecurinine blocked the inhibitory action of GABA while having no effect on that of glycine. Allo-and virosecurinine were much less active as GABA receptor antagonists in this test. These results suggest that, like bicuculline, securinine and dihydrosecurinine are selective antagonists of GABA recognition sites on mammalian central neurons.
Excitatory amino acid antagonists protect mice against seizures induced by bicuculline
Brain Research, 1990
The effects of excitatory amino acid antagonists on convulsions induced by intracerebroventricular (i.c.v.) or systemic (s.c.) administration of the ),-aminobutyric acid A (GABAA) antagonist bicucuUine (BIC) were tested in mice. 3-((+)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP), 2-amino-7-phosphonoheptanoate (AP7) and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate (MK-801) were used as representatives of N-methyl-D-aspartate (NMDA) antagonists, y-D-Glutamylaminomethylsulphonate (~,-D-GAMS) typified a preferential kainate (KA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) represented a preferential quisqualate (QA) antagonist, and kynurenic acid (KYNA) was used as a mixed NMDA/KA antagonist. Bicuculline methiodide (BMI) induced clonic convulsions following i.c.v, administration with a CDso of 0.183 nmol (range 0.164-0.204). The excitatory amino acid antagonists blocked clonic seizures induced by BMI in the dose of 0.224 nmol (approximately CD97) when coinjected into the lateral ventricle. CPP (EDs0 0.0075 nmol) was the most potent anticonvulsant and was followed by AP7 (0.182 nmol), MK-801 (0.22 nmol), ?'-o-GAMS (0.4 nmol), KYNA (1.7 nmol) and CNQX (5.17 nmol). Muscimol (MSC), the GABA A agonist, blocked BMI-induced seizures with an EDso of 0.25 nmol. Systemic (s.c.) administration of BIC induced in mice generalized seizures with a CDso of 2.2 mg/kg (range 1.9-2.5) for clonus and CDso of 2.4 mg/kg (range 2.2-2.7) for tonus. The seizures induced by s.c. injection of BIC in the dose of 3.2 mg/kg (approximately CD97 ) were blocked by pretreatment (i.p.) with the NMDA antagonists MK-801 (EDso 0.075 mg/kg for clonus and 0.044 mg/kg for tonus), CPP (7.743 mg/kg for clonus and 0.032 mg/kg for tonus) and CGS 19755 (> 10 mg/kg for clonus and 3.01 mg/kg for tonus). The GABA A agonist MSC had no effect on clonus (> 2.5 mg/kg) and prevented mice from tonus with an EDso of 1.77 mg/kg. These results suggest an important role of excitation mediated by dicarboxylic amino acids in the pathogenesis of seizures triggered by bicucuiline in mice.
Effects of some GABAergic agents on quinine-induced seizures in mice
Experientia, 1992
The effects of some GABAergic agents on seizures induced by quinine were studied in mice. Muscimol, AOAA, DABA and baclofen significantly protected mice against quinine-induced convulsions. BicucuUine effectively enhanced quinine-induced convulsions, and significantly attenuated the protective effects of muscimol, AOAA and DABA against convulsions induced by quinine. Diazepam and phenobarbitone significantly protected mice against convulsions induced by quinine. However, phenytoin did not affect quinine-induced seizures to any significant degree. These results indicate that the convulsant effect of quinine may be due to a disturbance in the status of the GABAergic system.
Journal of Pharmacology and Experimental Therapeutics
Ganaxolone (CCD 1042) is a 3-methyl-substituted analog of the endogenous neuroactive steroid 3␣-hydroxy-5␣-pregnan-20-one. Ganaxolone inhibited binding of the ␥-aminobutyric acid (GABA) A receptor-chloride channel ligand t-[ 35 S]butylbicyclophosphorothionate (IC 50 of 80 nM) and enhanced binding of the benzodiazepine site ligand [ 3 H]flunitrazepam (EC 50 of 125 nM) and the GABA site ligand [ 3 H]muscimol (EC 50 of 86 nM), consistent with activity as a positive allosteric modulator of the GABA A receptor. Electrophysiological recordings showed that, whereas nanomolar concentrations of ganaxolone potentiated GABA-evoked chloride currents in Xenopus oocytes expressing the human GABA A receptor subunits ␣11␥2 L , ␣21␥2 L or ␣31␥2 L , direct activation of chloride flux occurred to a limited extent only at micromolar concentrations. Ganaxolone was effective in nontoxic doses against clonic convulsions induced by s.c. pentylenetetrazol administration in mice and rats (ED 50 values of 4.3 and 7.8 mg/kg i.p., respectively). Ganaxolone also exhibited potent anticonvulsant activity against seizures induced by s.c. bicuculline (ED 50 of 4.6 mg/kg i.p.), i.p. TBPS (ED 50 of 11.7 mg/kg i.p.) and i.p. aminophylline (ED 50 of 11.5 GABA-containing neurons are the predominant inhibitory neural elements within the brain. Correspondingly, GABAmediated inhibition plays a critical role in the epileptic process by contributing to the termination of the ictal discharge and limiting the spread of hyperexcitability. Potentiation of GABAergic inhibitory function has therefore served as the rational basis for a number of programs targeted toward the discovery of novel antiepileptic agents .
Studies on the neuropharmacological activity of bicuculline and related compounds
Brain Research, 1976
Bicuculline and 3 chemical derivatives were assayed on a variety of biological systems. Consistent with reports of studies on other animals, some of these compounds caused convulsions in insects and blocked inhibitory postsynaptic potentials in insect muscle. They all potently inhibited mouse brain acetylcholinesterase. Bicuculline and its analogs inhibited the binding of GABA in vitro to sites in crayfish muscle membranes which have properties of receptor sites; this site of action could explain the activity of bicuculline at arthropod neuromuscular junctions. These compounds, at high concentrations (over 100/~M), also inhibited GABA uptake by mouse brain homogenates at 0 °C apparently non-competitively. Bicucine methyl ester inhibited GABA transport by brain at 37 °C, consistent with non-specific membrane effects at high concentrations of drug. These and other observations cast doubt upon the specificity of bicuculline-like compounds for action on GABA synapses, especially for in vitro studies at high drug concentrations (over 10 #M). The neuroactivity of low doses of bicuculline is apparently not explained by these in vitro effects, and could very well be due to inhibition of GABA synapses at either receptor or ionophore sites. At physiological conditions of pH and temperature, bicuculline is hydrolyzed at its lactone moiety to the less active compound bicucine; this could lead to underestimates of the biological activity of bicuculline. More stable analogs studied so far are not more potent, however.