MDL 26,479: a potential cognition enhancer with benzodiazepine inverse agonist‐like properties

Miller, Jerry A.; Dudley, Mark W.; Kehne, John H.; Sorensen, Stephen M.; Kane, John M.

doi:10.1111/j.1476-5381.1992.tb14466.x

Cited by 22 publications

(11 citation statements)

References 55 publications

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“…[29][30][31][32] As BZR and neurons measured by FMZ or IMZ are preserved in the early stages of AD, the patients may be treatable with those cognition enhancers having benzodiazepine inverse agonist-like properties. [21][22][23][24][25][26][27][28][29][30][31] It is also suggested that benzodiazepines may have protective effects against AD based on epidemiological evidence of an association between benzodiazepine use and the occurrence of AD and vascular dementia in 668 individuals. 43 The in vivo measurement of density of BZR may provide the indication of the drug medication for AD patients.…”

Section: Benzodiazepine Receptor In Alzheimermentioning

confidence: 99%

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Preserved benzodiazepine receptors in Alzheimer’s disease measured with C-11 flumazenil PET and I-123 iomazenil SPECT in comparison with CBF

et al. 1999

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This study evaluates the regional cerebral blood flow (CBF) with H2(15)O-PET and the distribution of central benzodiazepine receptor (BZR) with C-11 flumazenil (FMZ) by PET and I-123 iomazenil (IMZ) by SPECT in Alzheimer's disease (AD). In AD, whereas the CBF was diminished in the frontal, temporal, parietal, and occipital cortex, the distribution volume of FMZ and delayed activity of IMZ were relatively preserved in these cortices, suggesting that the BZR reduction, reflecting neuronal loss, is less prominent than the CBF suppression. The mini-mental state examination score (MMS) was weakly correlated with the CBF in the parietal cortex but not with BZR. It is speculated that the neuronal density reflected by BZR is less impaired than the neuronal function assessed with blood flow in the association cortex of AD. High correlation was found between the uptake of FMZ and the delayed activity of IMZ. The delayed image of IMZ-SPECT is clinically useful to evaluate the preservation of neuronal density in the affected temoporoparietal association cortex in AD.

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Section: Benzodiazepine Receptor In Alzheimermentioning

confidence: 99%

“…Other investigators reported a more prominent reduction in IMZ uptake than CBF decrease measured by HMPAO in patients with AD. 28 As cognition enhancers in relation to benzodiazepine receptors have been proposed as a treatment of AD, [29][30][31][32] in vivo evaluation of BZR is becoming more important.…”

Section: Introductionmentioning

confidence: 99%

Preserved benzodiazepine receptors in Alzheimer’s disease measured with C-11 flumazenil PET and I-123 iomazenil SPECT in comparison with CBF

et al. 1999

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“…Previous experiments have provided evidence for the beneÞcial behavioral e¤ects of benzodiazepine receptor weak or selective inverse agonists in humans and animals pretreated with scopolamine (Duka et al 1987;Kumar et al 1988;Deacon et al 1990;Holley et al 1992;Mazurkiewicz et al 1992;Miller et al 1992;Prather et al 1992). ZK93426 (ethyl-5-isopropoxy-4-methyl-6-carboline-3-carboxylate), which possesses more inverse agonist activity than RO 15-1788 has been shown to enhance attentional abilities in human volunteers tested with a logical reasoning task and a picture-di¤erences task.…”

Section: Discussionmentioning

confidence: 97%

Effects of S-8510, a benzodiazepine receptor partial inverse agonist, on event-related potentials (P300) in monkeys

et al. 1999

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The present study investigated the effects of a novel benzodiazepine inverse agonist, S-8510 [2-(3-isoxazolyl)-3, 6, 7, 9-tetrahydroimidazo [4, 5-d] pyrano [4,3-b] pyridine monophosphate monohydrate], on the P300 components of the event-related potential (ERP) in monkeys. Late positive potentials (P300-like potentials) from the cortex (Pz) and hippocampus recorded using the auditory oddball paradigm in combination with electrical reinforcement can be measured in rhesus monkeys. The latency of this P300-like potential recorded from the monkey cortex was 330 ms, and the amplitude was 13 microV. It was prolonged in both the cortex (Pz) and hippocampus by SC injection of 10 microg/kg scopolamine, a muscarinic receptor antagonist. Oral administration of S-8510 (3, 10 mg/kg) had no effect on the latency in normal monkeys. However, S-8510 reversed the scopolamine-induced prolongation of P300-like potentials on the cortex (Pz) and hippocampus. These results show that S-8510 can attenuate the effects induced by scopolamine on P300-like potentials associated with cognitive function in monkeys, suggesting that S-8510 may be useful as a therapeutic drug in disease-associated cognitive dysfunctions of the central nervous system.

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“…MDL 26479 (Suritozole) is a negative modulator at GABA A receptors. This drug is similar to other benzodiazepine (BZD) receptor inverse agonists, however it lacks proconvulsive or axiogenic properties [85]. Previous research has shown that MDL 26479 increases cholinergic transmission and enhances cognition in animals [86,87].…”

Section: Gamma-aminobutyric Acid (Gaba) Systemmentioning

confidence: 97%

“…This would support previous work that shows beneficial effects of cholinergic agonists on cognitive outcome after TBI. Importantly, MDL 26479 may also affect other neurotransmitters systems and be influential in long-term potentiation (LTP) [85]. In remains unclear as to whether MDL 26479 did not attenuate cognitive deficits in the delayed administration group because of the delayed postinjury interval or fewer total drug injections.…”

Section: Gamma-aminobutyric Acid (Gaba) Systemmentioning

confidence: 99%

A review of pharmacological treatments used in experimental models of traumatic brain injury

Kokiko

Hamm

2007

Brain Injury

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Understanding the relationship between neural disturbances and functional deficits following brain injury is challenging. Cognitive impairment may be the result of a single event or multiple events that occur after the initial insult. Increasing neuronal activity during the chronic phase of injury seems to be an effective treatment strategy for facilitating cognitive recovery. Pharmacological agents do not necessarily display the same effects in an injured brain as in a non-injured brain. Thus, further research is needed to establish the effectiveness of rehabilitative drug treatments.

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MDL 26,479: a potential cognition enhancer with benzodiazepine inverse agonist‐like properties

Abstract: 1 The present study investigated biochemical, electrophysiological and behavioural properties of the novel cognition enhancer, MDL 26,479 (5-(3-fluorophenyl)-2,4,-dimethyl-3H-1,2,4-triazole-3-thione). 2 The 5-aryl-1,2,4-triazole, MDL 26,479, potently (0.22

Cited by 22 publications

References 55 publications

Preserved benzodiazepine receptors in Alzheimer’s disease measured with C-11 flumazenil PET and I-123 iomazenil SPECT in comparison with CBF

Preserved benzodiazepine receptors in Alzheimer’s disease measured with C-11 flumazenil PET and I-123 iomazenil SPECT in comparison with CBF

Effects of S-8510, a benzodiazepine receptor partial inverse agonist, on event-related potentials (P300) in monkeys

A review of pharmacological treatments used in experimental models of traumatic brain injury

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