The Effect of a New Water-Soluble Sedative-Hypnotic Drug, JM-1232(−), on Long-Term Potentiation in the CA1 Region of the Mouse Hippocampus

Takamatsu, Isao; Sekiguchi, Masayuki; Yonamine, Ryuji; Wada, Keiji; Kazama, Tomiei

doi:10.1213/ane.0b013e3182291782

Cited by 7 publications

(6 citation statements)

References 32 publications

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“…Not only JM-1232(-) but also other benzodiazepines might well produce similar results to those seen in the present study. However, JM-1232(-) has a short duration of action, which makes it more suitable for use as a supplementary drug [25].…”

Section: Discussionmentioning

confidence: 99%

JM-1232(−) and propofol, a new combination of hypnotics with short-acting and non-cumulative preferable properties

et al. 2021

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Drug interactions are significant in anesthesiology because drug combinations can potentially possess novel properties. The pharmacological advantages of a new combination of the benzodiazepine receptor agonist JM-1232(-) and propofol were investigated in mice. Male adult mice were administered JM-1232(-) or propofol or combinations of the two drugs intravenously. Loss of the righting reflex was evaluated as achieving hypnosis, and the time until recovery of the reflex was measured as hypnosis time. After determining the ED 50 , doses double and triple the ED 50 of propofol were injected with JM-1232(-) to compare hypnosis time. The injections were repeated four times, and the hypnosis times were compared. Flumazenil was administered separately immediately after the last dose was injected. The ED 50 values ([95% confidence interval]) for hypnosis were 3.76 [3.36-4.10] for JM-1232(-) and 9.88 [8.03-11.58] mg kg-1 for propofol. Co-administration of 0.5 and 1 mg kg-1 JM-1232(-) reduced the ED 50 values of propofol to 1.76 [1.21-2.51] and 1.00 [0.46-1.86] mg kg-1 , respectively. The drug combination for hypnosis produced a supra-additive interaction. Hypnosis time was significantly shorter in the groups given the mixtures compared to each hypnotic administered alone. After repeated injections, hypnosis time with the mixtures showed smaller prolongation than that with the 4 hypnotic alone. Flumazenil completely restored the recovery time after anesthesia. The combination of JM-1232(-) and propofol showed a supra-additive interaction, and the reduced hypnotic dose contributed to a faster recovery even after multiple injections.

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Section: Discussionmentioning

confidence: 99%

JM-1232(−) and propofol, a new combination of hypnotics with short-acting and non-cumulative preferable properties

et al. 2021

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“…[30] Although structurally not a benzodiazepine, JM-1232 (-) allosterically modulates GABA A receptor in a manner that seems to be identical to benzodiazepines and its activity can be inhibited by flumazenil, strongly suggesting that it binds to the same site on the GABA A receptor as classic benzodiazepines. [595838] In addition to its sedative–hypnotic actions, JM-1232 (-) has been shown in animals to possess antinociceptive properties and have a therapeutic index of >38.5, which indicates a safety margin that is greater than propofol, midazolam, thiopental, and even etomidate. [30388]…”

Section: Rational Designmentioning

confidence: 99%

Anesthetic drug development: Novel drugs and new approaches

Chitilian

Eckenhoff²,

Raines³

2013

Surg Neurol Int

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The ideal sedative–hypnotic drug would be a rapidly titratable intravenous agent with a high therapeutic index and minimal side effects. The current efforts to develop such agents are primarily focused on modifying the structures of existing drugs to improve their pharmacodynamic and pharmacokinetic properties. Drugs currently under development using this rational design approach include analogues of midazolam, propofol, and etomidate, such as remimazolam, PF0713, and cyclopropyl methoxycarbonyl-etomidate (MOC-etomidate), respectively. An alternative approach involves the rapid screening of large libraries of molecules for activity in structural or phenotypic assays that approximate anesthetic and target receptor interactions. Such high-throughput screening offers the potential for identifying completely novel classes of drugs. Anesthetic drug development is experiencing a resurgence of interest because there are new demands on our clinical practice that can be met, at least in part, with better agents. The goal of this review is to provide the reader with a glimpse of the novel anesthetic drugs and new developmental approaches that lie on the horizon.

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“…The effects of JM-1232(-) are inhibited by flumazenil. 13 In mice, the 50% hypnotic dose (HD 50 ) was estimated at 3.12 mg/kg whereas the therapeutic index (LD 50 /HD 50 ) was more than 38.5. 12 Intrathecal and intraperitoneal administration of JM-1232(-) is nociceptive in rat thermal tail withdrawal response and tail pressure models.…”

Section: What This Article Tells Us That Is Newmentioning

confidence: 99%

First Human Administration of MR04A3

Sneyd

Rigby-Jones²,

Cross³

et al. 2012

Anesthesiology

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The Effect of a New Water-Soluble Sedative-Hypnotic Drug, JM-1232(−), on Long-Term Potentiation in the CA1 Region of the Mouse Hippocampus

Abstract: JM-1232(-) enhances synaptic inhibition and impairs LTP and paired-pulse facilitation in area CA1 of the mouse hippocampus. These effects were mediated by benzodiazepine binding sites on γ-aminobutyric acid A receptors.

Cited by 7 publications

References 32 publications

JM-1232(−) and propofol, a new combination of hypnotics with short-acting and non-cumulative preferable properties

JM-1232(−) and propofol, a new combination of hypnotics with short-acting and non-cumulative preferable properties

Anesthetic drug development: Novel drugs and new approaches

First Human Administration of MR04A3

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