Peninsula Medical School, University of Plymouth, Plymouth, United Kingdom.
Anesthesiology. 2012 Feb;116(2):385-95. doi: 10.1097/ALN.0b013e318242b2af.
JM-1232(-), (-)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-phenyl-3,5,6,7-tetrahydrocyclopenta [f]isoindol-1(2H)-one, molecular formula, C(24)H(27)N(3)O(2); molecular weight, 389.49, is a novel isoindoline water-soluble benzodiazepine receptor agonist with favorable anesthetic/sedative properties in animals. MR04A3 is a 1% aqueous presentation of JM-1232(-).
In Step 1, healthy male volunteers received 10-min infusions of MR04A3, 0.05, 0.1, 0.2, 0.4, and 0.8 mg/kg, with three MR04A3 subjects and one placebo subject per dose concentration. In Step 2, doses were 0.025, 0.05, 0.075, 0.1, 0.2, 0.3, and 0.4 mg/kg over 1 min with six MR04A3 subjects and one placebo subject per dose concentration.
Hypnotic effects of MR04A3 were seen at all dose concentrations in Step 1 and at doses of 0.075 mg/kg or more in Step 2. Central nervous system effect was seen at all dose concentrations with larger doses of MR04A3 producing a deeper and longer reduction in bispectral index. Ramsay sedation scores were increased with higher doses causing sedation and then unresponsiveness. The adverse event profile of subjects receiving MR04A3 was similar to that of subjects given placebo except that some subjects receiving MR04A3 developed upper airway obstruction while sedated. This responded to simple maneuvers (i.e., chin lift). Changes in systolic arterial blood pressure and heart rate were minimal.
MR04A3 is hypnotic in man with a satisfactory hemodynamic and safety profile.
JM-1232(-)，(-)-3-[2-(4-甲基-1-哌嗪基)-2-氧代乙基]-2-苯基-3,5,6,7-四氢环戊[f]异吲哚-1(2H)-酮，分子式为 C(24)H(27)N(3)O(2)，分子量为 389.49，是一种新型的异吲哚啉类水溶性苯二氮䓬受体激动剂，在动物中具有良好的麻醉/镇静特性。MR04A3 是 JM-1232(-)的 1%水溶液制剂。
在第 1 步中，健康男性志愿者接受 10 分钟的 MR04A3 输注，剂量分别为 0.05、0.1、0.2、0.4 和 0.8 mg/kg，每个剂量浓度有 3 个 MR04A3 受试者和 1 个安慰剂受试者。在第 2 步中，剂量为 0.025、0.05、0.075、0.1、0.2、0.3 和 0.4 mg/kg，输注时间为 1 分钟，每个剂量浓度有 6 个 MR04A3 受试者和 1 个安慰剂受试者。
在第 1 步中，MR04A3 在所有剂量浓度下均显示出催眠作用，在第 2 步中，在 0.075 mg/kg 或更高剂量下也显示出催眠作用。中枢神经系统作用在所有剂量浓度下均可见，较大剂量的 MR04A3 可使脑电双频指数（bispectral index）深度和持续时间更长。Ramsay 镇静评分随着剂量的增加而升高，导致镇静甚至无反应。接受 MR04A3 治疗的受试者的不良事件谱与接受安慰剂的受试者相似，除了一些接受 MR04A3 治疗的受试者在镇静时发生上呼吸道阻塞外。这种情况对简单的操作（如抬起下巴）有反应。收缩压和心率的变化很小。
MR04A3 对人体具有催眠作用，具有满意的血液动力学和安全性特征。
