Timed Intravenous Infusion of Metrazol and Strychnine for Testing Anticonvulsant Drugs.

Orloff, Marshall J.; Williams, Harry L.; Pfeiffer, Carl C.

doi:10.3181/00379727-70-16891

Cited by 119 publications

(35 citation statements)

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“…The test compound or 1% tragacanth was administered orally to groups of 10 male mice, 1 h before subcutaneous injection of reserpine (5 mg/kg); 2 h after the reserpine injection, a 0.45% solution of pentamethylenetetrazole was injected intravenously at the rate of 0.05 ml every 10 s (Orloff, Williams & Pfeiffer, 1949). The volume of solution producing the tonic extensor component of the convulsion was noted.…”

Section: Methodsmentioning

confidence: 99%

Fluvoxamine, a Specific 5‐hydroxytryptamine Uptake Inhibitor

Claassen

Davies

Hertting

et al. 1977

British J Pharmacology

173

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IOn the basis of both in vitro and in vivo experiments fluvoxamine has been characterized as a potential anti-depressant drug with almost exclusively 5-hydroxytryptamine (5-HT) uptake inhibiting properties. 2 Fluvoxamine is effective in inhibiting 5-HT uptake by blood platelets and brain synaptosomes. Due to inhibition of the membrane pump the compound prevents 5-HT depletion by the tyraminederivatives H 75/12 and H 77/77. As a result of the interference with the neuronal re-uptake mechanism for 5-HT, fluvoxamine produces a decreased 5-HT turnover in the brain. Effects of 5-hydroxytryptophan (5-HTP) are potentiated in mice and in combination with pargyline, fluvoxamine induces 5-HT-like behavioural effects. 3 In contrast to tricyclic antidepressants, noradrenaline uptake processes are either unaffected or only slightly inhibited by fluvoxamine. The noradrenaline depleting effects of tyramine derivatives are not influenced by fluvoxamine. Reserpine effects, such as ptosis are affected only at very high doses of the test compound. The antagonism by fluvoxamine of the reserpine-induced lowering of the pentamethylenetetrazole convulsive threshold can be regarded as due to an effect upon 5-HT uptake. In contrast to the effects of desmethylimipramine and imipramine, no stimulatory effects are found in rats when rapidly acting reserpine-like compounds are given following a dose of fluvoxamine.

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Section: Methodsmentioning

confidence: 99%

Fluvoxamine, a Specific 5‐hydroxytryptamine Uptake Inhibitor

Claassen

Davies

Hertting

et al. 1977

British J Pharmacology

173

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“…to cohorts of 10 mice 2 hours prior to the test. Mice were challenged with 0.5% heparinized Metrazol solution [5 mg/ml; pentylenetetrazol (PTZ), SigmaAldrich, St. Louis, MO], infused at a constant rate of 0.34 ml/min into a lateral tail vein of an unrestrained mouse (Orloff et al, 1949;White et al, 1997). The time in seconds from the start of the infusion to the appearance of the "first twitch," and then to the onset of sustained clonus, was recorded.…”

Section: Anticonvulsant Studiesmentioning

confidence: 99%

Discovery and Characterization of AMPA Receptor Modulators Selective for TARP- 8

Maher

Ravula

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

153

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Members of the a-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptors mediate the majority of fast synaptic transmission within the mammalian brain and spinal cord, representing attractive targets for therapeutic intervention. Here, we describe novel AMPA receptor modulators that require the presence of the accessory protein CACNG8, also known as transmembrane AMPA receptor regulatory protein g8 (TARP-g8). Using calcium flux, radioligand binding, and electrophysiological assays of wild-type and mutant forms of TARP-g8, we demonstrate that these compounds possess a novel mechanism of action consistent with a partial disruption of the interaction between the TARP and the pore-forming subunit of the channel. One of the molecules, 5-[2-chloro-6-(trifluoromethoxy)phenyl]-1,3-dihydrobenzimidazol-2-one (JNJ-55511118), had excellent pharmacokinetic properties and achieved high receptor occupancy following oral administration. This molecule showed strong, dose-dependent inhibition of neurotransmission within the hippocampus, and a strong anticonvulsant effect. At high levels of receptor occupancy in rodent in vivo models, JNJ-55511118 showed a strong reduction in certain bands on electroencephalogram, transient hyperlocomotion, no motor impairment on rotarod, and a mild impairment in learning and memory. JNJ-55511118 is a novel tool for reversible AMPA receptor inhibition, particularly within the hippocampus, with potential therapeutic utility as an anticonvulsant or neuroprotectant. The existence of a molecule with this mechanism of action demonstrates the possibility of pharmacological targeting of accessory proteins, increasing the potential number of druggable targets.

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“…Various doses of each substance were administered to groups of mice until at least two points were established between the limits of 0 and 100% protection. Minimal motor impairment was assessed by the rotarod test (Orlof et al, 1949). For this study, groups of six to eight mice per dose were tested for their ability to maintain balance on a rotating rod (6 rpm).…”

Section: Anticonvulsant Testingmentioning

confidence: 99%

Correlation between Anticonvulsant Activity and Inhibitory Action on Glial γ-Aminobutyric Acid Uptake of the Highly Selective Mouse γ-Aminobutyric Acid Transporter 1 Inhibitor 3-Hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole and ItsN-Alkylated Analogs

White

Sarup

Bolvig

et al. 2002

J Pharmacol Exp Ther

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The inhibitory effect of 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole (exo-THPO) and its N-methylated (N-methylexo-THPO) and N-ethylated (N-ethyl-exo-THPO) analogs, derived from ␥-aminobutyric acid (GABA) and 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO) on GABA transport was investigated using cultured neocortical neurons (GABAergic) and astrocytes and cloned mouse GABA transporters GAT1-4 expressed in human embryonic kidney (HEK) 293 cells. Anticonvulsant activity was assessed after i.c.v. administration to Frings audiogenic seizure-susceptible mice. Anticonvulsant activity of the O-pivaloyloxymethyl prodrug of N-methyl-exo-THPO was assessed after i.p. administration. Results from these studies were compared with those obtained from similar studies with the novel anticonvulsant drug tiagabine, which acts via inhibition of GABA transport. exo-THPO and its N-alkyl analogs inhibited neuronal, astrocytic, and GAT1-mediated GABA transport but not GABA uptake mediated by GAT2-4. N-Methyl-exo-THPO was 8-fold more potent as an inhibitor of astrocytic versus neuronal GABA uptake. The IC 50 value for inhibition of GABA uptake by GAT1 closely reflected its IC 50 value for inhibition of neuronal uptake. Tiagabine was approximately 1000-fold more potent than exo-THPO and its alkyl derivatives as an inhibitor of GABA uptake in cultured neural cells and GAT1-expressing HEK 293 cells. exo-THPO, its alkylated analogs, and tiagabine displayed a timeand dose-dependent inhibition of audiogenic seizures after i.c.v. administration. N-Methyl-exo-THPO was the most potent anticonvulsant among the exo-THPO compounds tested and only slightly less potent than tiagabine. The findings suggest a correlation between anticonvulsant efficacy and selective inhibition of astroglial GABA uptake. Furthermore, results obtained with the N-methyl-exo-THPO prodrug demonstrate the feasibility of developing a glial-selective GABA uptake inhibitor with systemic bioavailability.Within the central nervous system (CNS), ␥-aminobutyric acid (GABA) serves as the principal inhibitory neurotransmitter. Once released from the presynaptic terminal, GABA binds to both presynaptic and postsynaptic GABA receptors, which are coupled to either a G protein-associated K ϩ channel (GABA B receptors) or form Cl Ϫ -permeable ion channels (GABA A receptors). Alterations in GABA-ergic function have been implicated in a number of CNS disorders, including epilepsy, migraine, bipolar disorder, anxiety, and depression. As such, it is not surprising that the GABA A receptor has been the target for numerous therapeutic entities, including the benzodiazepines, barbiturates, and neurosteroids. Collec-

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Timed Intravenous Infusion of Metrazol and Strychnine for Testing Anticonvulsant Drugs.

Cited by 119 publications

References 0 publications

Fluvoxamine, a Specific 5‐hydroxytryptamine Uptake Inhibitor

Fluvoxamine, a Specific 5‐hydroxytryptamine Uptake Inhibitor

Discovery and Characterization of AMPA Receptor Modulators Selective for TARP- 8

Correlation between Anticonvulsant Activity and Inhibitory Action on Glial γ-Aminobutyric Acid Uptake of the Highly Selective Mouse γ-Aminobutyric Acid Transporter 1 Inhibitor 3-Hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole and ItsN-Alkylated Analogs

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