The morpholino-acetic acid analogue Sch 50911 is a selective GABAB receptor antagonist in rat neocortical slices

Ong, Jennifer; Marino, Victor; Parker, David; Kerr, Donald; Blythin, David J.

doi:10.1016/s0014-2999(98)00723-7

Cited by 19 publications

(12 citation statements)

References 22 publications

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“…Clearly, there was a less than additive effect, the mechanism of which is unknown. The GABA B receptor antagonist SCH 50911 (Ong et al 1998) did not significantly affect the interactions between baclofen and damphetamine, although on its own, it slightly increased heart rate over the dose-range of 3.0-10.0 mg/kg. Direct injection of d-amphetamine into the nucleus accumbens releases dopamine and produces an increase in locomotion, often characterised by coordinated forward locomotion, rearing and sniffing (Arnt 1983).…”

Section: Discussionmentioning

confidence: 83%

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Modification of d-amphetamine-induced responses by baclofen in rats

Phillis

Ong

White³

et al. 2000

Psychopharmacology

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The results of the present study suggest that stimulation of GABAB receptors by baclofen completely blocks the locomotor stimulatory effects of d-amphetamine. Baclofen did not significantly modify the increase in heart rate produced by d-amphetamine and decreased body temperature, both alone and in combination with d-amphetamine. GABAB receptor ligands may well have potential as pharmacotherapies in the treatment of amphetamine abuse and dependence.

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Section: Discussionmentioning

confidence: 83%

“…These effects were antagonised by SCH 50911 (Ong et al 1998), indicating that GABA B receptors were involved in the suppression of spontaneous activity. SCH 50911 alone, however, was without effect on activity.…”

Section: Discussionmentioning

confidence: 97%

Modification of d-amphetamine-induced responses by baclofen in rats

Phillis

Ong

White³

et al. 2000

Psychopharmacology

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“…The potentiating action of thymol on [ 3 H]-GABA release is reminiscent of the action of the GABA B receptor antagonist Sch 50911, which markedly increases the release of [ 3 H]-GABA, an effect attributed to its inhibition of GABA B autoreceptors responsible for regulating release of the transmitter. 20 However, thymol is much less potent than Sch 50911 and although in the presence of baclofen its potentiating effect was reduced, it is unclear whether thymol is a specific GABA B autoreceptor antagonist. In contrast, 4MP, an analogue of thymol, inhibited the stimulation-induced overflow of [ 3 H]-GABA in a concentration-dependent manner, with a similar potency to baclofen.…”

Section: Discussionmentioning

confidence: 99%

“…The GABA B receptor agonists, such as baclofen, activate presynaptic GABA B autoreceptors and inhibit electrically evoked [ 3 H]-GABA release, whereas the GABA B receptor antagonist Sch 50911 markedly increases the release of GABA 20. This action of Sch 50911 on GABA release is attributed to its inhibition of GABA B autoreceptors responsible for regulating release of the transmitter.…”

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confidence: 99%

Pharmacological actions of thymol and an analogue at GABA_B autoreceptors

Parker

Marino

Ong

2014

Clin Exp Pharma Physio

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GABAB autoreceptors inhibit release of GABA from GABAergic nerve terminals. Agonists of these receptors (e.g. baclofen) inhibit, whereas antagonists (e.g. (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; Sch 50911) enhance release of the transmitter. The actions of thymol (2-isopropyl-5-methylphenol) and the structurally related compound 2-tert-butyl-4-methylphenol, (4MP) on the release of [(3) H]-GABA were examined in rat neocortical slices where the GABAergic nerves had been preloaded with [(3) H]-GABA and subsequently stimulated electrically on two occasions (S1 and S2 ). Test agents, baclofen and Sch 50911 were added to the superfusion medium prior to the second period of stimulation (S2 ). Stimulation-induced overflow (SIO) of [(3) H]-GABA as a consequence of these stimulations (SIO1 and SIO2 ) were calculated and the effects of agents determined by comparing the SIO2 /SIO1 ratio in the presence of each agent with that in control tissue. Thymol potentiated the release of [(3) H]-GABA (EC50 170 μmol/L), an action reversed by baclofen (2 μmol/L). Baclofen alone had little effect on GABA release. Release of [(3) H]-GABA was inhibited by 4MP (IC50 3 μmol/L) and this effect was blocked by Sch 50911 (10 μmol/L). Alone, Sch 50911 markedly potentiated the release of GABA. These results imply that 4MP is an agonist of GABAB autoreceptors; however, further studies are needed to confirm that thymol is indeed a GABAB autoreceptor antagonist. Of interest are structural differences in these agents. Thymol has a propyl group in the ortho position relative to the phenolic hydroxyl, whereas in 4MP this is a butyl group and the methyl group moves from position 5 to 4. Whether one or both of these changes was responsible for the above actions is unknown.

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“…suppresses absence seizures. Sch 54679 (5-(S,R)-hydroxymethyl-5-methylmorpholynyl-2-(R,S)-acetic acid) and Sch 51342 (2-(R,S)-5-[spirocyclopentyl]-morpholynylacetic acid), two derivatives of Sch 50911 differing in their 5-alkyl substituents on the morpholino-ring, likewise possess antagonistic actions at GABA B auto-and heteroreceptors, and may soon be tested for their efficacy in epilepsy [71,72]. molecule is accompanied by cotransport of two Na + and one Cl - [85].…”

Section: Thementioning

confidence: 99%

The Inhibitory Neural Circuitry as Target of Antiepileptic Drugs

Böhme¹,

Lüddens²

2001

CMC

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Impairments and defects in the inhibitory neurotransmission in the CNS can contribute to various seizure disorders, i.e., gamma-aminobutyric acid (GABA) and glycine as the main inhibitory neurotransmitters in the brain play a crucial role in some forms of epilepsy. Recent advances in deciphering the molecular basis of the GABAergic and glycinergic systems has been achieved by means of cloning techniques and gene targeting strategies in animals, contributing to the understanding of drug action. As well, several anticonvulsive substances emerged which target key molecules of the inhibitory systems. Employment of recombinant expression systems, including, but not restricted to the inhibitory circuitry, will further facilitate drug screening and rational approaches to design novel specific antiepileptic drugs, which act highly efficiently to prevent or reduce generation and spread of seizures.

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The morpholino-acetic acid analogue Sch 50911 is a selective GABAB receptor antagonist in rat neocortical slices

Cited by 19 publications

References 22 publications

Modification of d-amphetamine-induced responses by baclofen in rats

Modification of d-amphetamine-induced responses by baclofen in rats

Pharmacological actions of thymol and an analogue at GABA_B autoreceptors

The Inhibitory Neural Circuitry as Target of Antiepileptic Drugs

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The morpholino-acetic acid analogue Sch 50911 is a selective GABAB receptor antagonist in rat neocortical slices

Cited by 19 publications

References 22 publications

Modification of d-amphetamine-induced responses by baclofen in rats

Modification of d-amphetamine-induced responses by baclofen in rats

Pharmacological actions of thymol and an analogue at GABAB autoreceptors

The Inhibitory Neural Circuitry as Target of Antiepileptic Drugs

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Product

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Pharmacological actions of thymol and an analogue at GABA_B autoreceptors