CNS 7056 - A novel ultra-short-acting benzodiazepine
CNS 7056 - A novel ultra-short-acting benzodiazepine
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DOI：
10.1097/01.anes.0000267503.85085.c0
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发表时间：
2007-07-01
期刊：
影响因子：
8.8
通讯作者：
Tilbrook, Gary S.
中科院分区：
文献类型：
--
作者：
Kilpatrick, Gavin J.;McIntyre, Margaret S.;Tilbrook, Gary S.
背景：一种新的苯二氮卓衍生物 CNS 7056 已被开发出来，其镇静特性优于现有药物，即更可预测的快速起效、镇静作用持续时间短和快速恢复特性。这一目标是通过使化合物易于通过酯酶代谢而实现的。作者现在报告 CNS 7056 的体外和体内概况。方法：使用放射性配体结合评估 CNS 7056 及其羧酸代谢物 CNS 7054 对苯二氮卓受体的亲和力及其选择性概况。使用全细胞膜片钳技术评估 CNS 7056 和咪达唑仑对 A 型 γ-氨基丁酸 (GABA(A)) 受体亚型 (α(1)β(2)gamma(2) α(2)beta(2)gamma(2)、α(3)beta(2)gamma(2)、α(5)beta(2)gamma(2)) 的活性。使用黑质网状部细胞外电生理学测量大鼠体内 CNS 7056 对脑苯二氮卓受体的活性。使用翻正反射丧失测试在啮齿动物中测量镇静特性。结果。 CNS 7056 以高亲和力与脑苯二氮卓位点结合。羧酸代谢物 CNS 7054 的亲和力低约 300 倍。 CNS 7056 和 CNS 7054 (10 μm) 对一系列其他受体没有亲和力。 CNS 7056 增强稳定转染 GABAA 受体亚型的细胞中的 GABA 电流。 CNS 7056 与咪达唑仑和其他经典苯二氮卓类药物一样，在 GABAA 受体亚型之间没有表现出明显的选择性。 CNS 7056（静脉注射）对黑质网状部神经元放电产生剂量依赖性抑制，并迅速恢复到基线放电率。 CNS 7056（静脉注射）导致啮齿类动物翻正反射丧失。翻正反射丧失的持续时间很短（< 10 分钟），并可通过氟马西尼预处理得到抑制。结论。 CNS 7065 是 GABAA 受体上苯二氮卓位点的高亲和力和选择性配体。 CNS 7056 不显示 GABAA 受体亚型之间的选择性。 CNS 7056 是一种对啮齿动物有效的镇静剂，作用持续时间短。氟马西尼抑制黑质网状部放电和抑制 CNS 7056 的作用表明它作用于大脑苯二氮卓受体。
Background: A new benzodiazepine derivative, CNS 7056, has been developed to permit a superior sedative profile to current agents, ie., more predictable fast onset, short duration of sedative action, and rapid recovery profile. This goal has been achieved by rendering the compound susceptible to metabolism via esterases. The authors now report on the profile of CNS 7056 in vitro and in vivo.Methods: The affinity of CNS 7056 and its carboxylic acid metabolite, CNS 7054, for benzodiazepine receptors and their selectivity profiles were evaluated using radioligand binding. The activity of CNS 7056 and midazolam at subtypes (alpha(1)beta(2)gamma(2) alpha(2)beta(2)gamma(2), alpha(3)beta(2)gamma(2), alpha(5)beta(2)gamma(2)) of the gamma-aminobutyric acid type A (GABA(A)) receptor was evaluated using the whole cell patch clamp technique. The activity of CNS 7056 at brain benzodiazepine receptors in vivo was measured in rats using extracellular electrophysiology in the substantia nigra pars reticulata. The sedative profile was measured in rodents using the loss of righting reflex test.Results. CNS 7056 bound to brain benzodiazepine sites with high affinity. The carboxylic acid metabolite, CNS 7054, showed around 300 times lower affinity. CNS 7056 and CNS 7054 (10 mu m) showed no affinity for a range of other receptors. CNS 7056 enhanced GABA currents in cells stably transfected with subtypes of the GABAA receptor. CNS 7056, like midazolam and other classic benzodiazepines, did not show clear selectivity between subtypes of the GABAA receptor. CNS 7056 (intravenous) caused a dose-dcpendent inhibition of substantia nigra pars reticulata neuronal firing and recovery to baseline firing rates was reached rapidly. CNS 7056 (intravenous) induced loss of the righting reflex in rodents. The duration of loss of righting reflex was short (< 10 min) and was inhibited by pretreatment with flumazenil.Conclusions. CNS 7065 is a high-affinity and selective ligand for the benzodiazepine site on the GABAA receptor. CNS 7056 does not show selectivity between GABAA receptor subtypes. CNS 7056 is a potent sedative in rodents with a short duration of action. inhibition of substantia nigra pars reticulata firing and the inhibition of the effects of CNS 7056 by flumazenil show that it acts at the brain henzodiazepine receptor.