Lemildipine (NB-818)
(Synonyms: 来米地平,NB-818; NPK-1886) 目录号 : GC32533
Lemildipine (NB-818) 是一种新型二氢吡啶钙进入阻滞剂。
Cas No.:94739-29-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
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Animal experiment: | Gerbils[1] Male Mongolian gerbils, weighing 50-80g, are used in this experiment. Lemildipine (3 mg/kg) or vehicle is administered intraperitoneally just after the recirculation. At 1, 2 or 4 weeks after ischemia, the animals are sacrificed, and the protective effect of Lemildipine (NB-818) is examined. Mice and Rats[2] Normal Wistar rats (NWR) and hypertensive model rats (spontaneously hypertensive rats (SHR), renal hypertensive rats (RHR) and DOCA-saline-induced hypertensive rats (DOC-Na-R)) of the male sex, weighing from 250 to 350 g, are used. Oral administration of Lemildipine in doses of 3, 10, 30 mg/kg for normal Wistar rats (NWR). Lethal dose of Lemildipine and Nifedipine is determined by the Litchfield-Wilcoxon method from the data of experiments using healthy mice and rats. Mice (male and female) weighing 20±2 g and male rats weighing from 150 to 220 g are used. These two kinds of animals are fed on solid food (Crea, CA-1) and water ad lib. The animal room temperature and humidity are controlled at 22±2°C and 55±5%, respecttively. No food except water is administered 24 hr before starting the experiments for oral administration of drugs. |
References: [1]. Kamei K, et al. Effect of a new calcium entry blocker, NB-818, on delayed neuronal death in the ischemic gerbil hippocampus. Jpn J Pharmacol. 1991 Jul;56(3):279-86. | |
Lemildipine is a new dihydropyridine calcium entry blocker.
Gerbils are treated intraperitoneally with Lemildipine (0.1-3 mg/kg) just after release of the occlusion. Four days after the ischemia, they are fixed by perfusing 10% buffered-formalin, and the neuronal cell density (NCD, cell/mm) in the CA1 subfield is estimated under microscopy. The average NCD in the ischemic control group is 43±10.8 cells/mm, whereas Lemildipine (3 mg/kg) significantly ameliorates DND with an average NCD of 143±24.2 cells/mm (P<0.01). In addition, Lemildipine (3 mg/kg) significantly inhibits delayed neuronal death (DND) at 1, 2 and 4 weeks after transient ischemia: the average NCD of the Lemildipine and ischemic control groups are 80±9.4 (P<0.01) and 43±7.7 cells/mm, 92±13.7 (P<0.05) and 52±9.3 cells/mm, and 57±5.0 (P<0.01) and 43±12.4 cells/mm, respectively. In this experiment, Lemildipine (NB-818) exhibits a protective effect on DND in the hippocampal CA1 subfield after transient forebrain ischemia, and its effect persisted for up to 4 weeks[1]. In normal Wistar rats (NWR), Lemildipine (NPK-1886) in doses of 3-30 mg/kg, p.o., produces a mild lowering of blood pressure. The depressor effect of Lemildipine is much the same as that of Nifedipine. In contrast, Lemildipine produces a significant decrease in the blood pressure of spontaneously hypertensive rats (SHR). Oral administration of Lemildipine in doses of 3, 10, 30 mg/kg produces a significant decrease in systolic blood pressure dose-dependently. The maximum decrease is observed 1-3 hr after administration. Comparing the hypotensive potency of Lemildipine and Nifedipine, their dose-response curves at the maximum response during the observation (for 24 hr) are analyzed by the least squares method, and the dose of 30% decrease in blood pressure from the control level (ED30) are used as a measure of their potency. Lemildipine is 1.4 times stronger than Nifedipine; the ED30 values of Lemildipine and Nifedipine are 10.2 mg/kg and 14.3 mg/kg, respectively[2].
[1]. Kamei K, et al. Effect of a new calcium entry blocker, NB-818, on delayed neuronal death in the ischemic gerbil hippocampus. Jpn J Pharmacol. 1991 Jul;56(3):279-86. [2]. Nagura J, et al. Cardiovascular effects of NPK-1886, a new dihydropyridine compound with calcium entry blocking activity. Jpn J Pharmacol. 1986 Mar;40(3):399-409.
| Cas No. | 94739-29-4 | SDF | |
| 别名 | 来米地平,NB-818; NPK-1886 | ||
| Canonical SMILES | O=C(C1=C(COC(N)=O)NC(C)=C(C(OC)=O)C1C2=CC=CC(Cl)=C2Cl)OC(C)C | ||
| 分子式 | C20H22Cl2N2O6 | 分子量 | 457.3 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1867 mL | 10.9337 mL | 21.8675 mL |
| 5 mM | 0.4373 mL | 2.1867 mL | 4.3735 mL |
| 10 mM | 0.2187 mL | 1.0934 mL | 2.1867 mL |
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In vitro assessment for vascular selectivity of a new dihydropyridine derivative, NB-818
Eur J Pharmacol 1996 Apr 22;301(1-3):99-106.PMID:8773452DOI:10.1016/0014-2999(96)00007-6.
The vascular selectivity of NB-818 (isopropyl methyl 2-carbamoyloxymethyl-6-methyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine -3, 5-dicarboxylate), a newly synthesized dihydropyridine derivative, was evaluated in in vitro experiments. NB-818 and nifedipine concentration dependently caused a relaxant effect in rabbit femoral arteries precontracted with 60 mM K+, a negative inotropic effect in guinea-pig papillary muscles, and a negative chronotropic effect in guinea-pig right atria. The onset of these inhibitory effects of NB-818 was much slower than that of nifedipine when compared at concentrations producing the same inhibition. The relaxant effect of NB-818 was about 10 times more potent than that of nifedipine, while the negative inotropic effect of NB-818 was about 100 times less potent than that of nifedipine. As a result, NB-818 showed about 300 times higher vascular selectivity than nifedipine. The two drugs exhibited a similar potency for the negative chronotropic effect. In a whole-cell configuration with voltage clamp, the blocking effect of NB-818 on L-type Ca2+ current (ICa) in guinea-pig ventricular cells appeared much more slowly than that of nifedipine and was hardly washed out. The potency of NB-818 to block ICa was markedly enhanced under depolarized conditions (i.e. at a holding potential of -30 mV) compared to that under polarized conditions (i.e. at a holding potential of -70 mV). Such a voltage-dependent blocking action on ICa was less pronounced for nifedipine. These results indicate that NB-818 is a slow-acting Ca2+ channel antagonist with much high vascular selectivity. Its vascular selectivity may be at least in part related to the marked voltage-dependent inhibition of ICa.
Effects of the calcium antagonist NB-818 on cerebral blood flow
Life Sci 1988;43(21):1715-23.PMID:3193855DOI:10.1016/0024-3205(88)90483-3.
The effects of intravenous injection of NB-818, isopropyl methyl 2-carbamoyloxymethyl-6-methyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5- dicarboxylate, on regional cerebral blood flow were studied in rabbits and Rhesus monkeys, using the hydrogen clearance technique. The above effects were compared with those of nicardipine and nimodipine. In rabbits, NB-818 (10 micrograms/kg i.v.) increased both cerebral cortical blood flow (rCBF) and cerebellar cortical blood flow by about 80% of the predrug level with a moderate decrease in mean arterial blood pressure, and no increase in skeletal muscle blood flow. The increase in cerebral blood flow with NB-818 was as great as that with nicardipine or nimodipine. In Rhesus monkeys, NB-818 (10-20 micrograms/kg i.v.) increased rCBF by about 30% of the predrug level, and its effect continued 30-60 min after dosing. The increase in rCBF with NB-818 was greater than that with nicardipine. The results from the present study indicate that NB-818 predominantly increases rCBF with a concomitant moderate hypotension, and its action is greater than that of nicardipine or nimodipine.
Stereo-selective calcium antagonistic and binding properties of the enantiomers of Lemildipine in vascular tissue of pigs and dogs
Arzneimittelforschung 1996 Nov;46(11):1045-53.PMID:8955863doi
Stereo-selective calcium antagonistic properties of the enantiomers of Lemildipine (CAS 94739-29-4, NB-818) were assessed in vascular tissues, including pig coronary artery and dog cerebral artery. Ca2+ antagonistic action of (-)-lemildipine was about 5 times and 100 times more potent than nifedipine and (+)-lemildipine, respectively. (-), (+), and (+/-)-lemildipine showed a slow onset and long duration of Ca2+ antagonistic action. Pretreatment with (-)-lemildipine and (+/-)-lemildipine for 30 min inhibited the contractions produced by 5-hydroxytryptamine and endothelin-1 with pD2 values between 6.0-8.5, whereas (+)-lemildipine and nifedipine were less potent. Of the Lemildipine enantiomers, (+)-lemildipine at a low concentration (1 nmol/l) had a slight but significant Ca2+ agonistic action. However, (+)-lemildipine had no apparent effect on the pCa-tension relationship in the dog basilar artery permeabilized with Staphylococcus aureus alpha-toxin. Enantiomers of Lemildipine as well as nifedipine competitively antagonized the specific binding of (+)-[3H]PN 200-110 (isradipine) to the membranes of pig coronary artery in the following order: (-)-lemildipine > nifedipine > (+/-)-lemildipine > (+)-lemildipine. These results suggest that the stereo-selective Ca2+ antagonistic actions of Lemildipine enantiomers and nifedipine assessed in the functional experiments were well correlated with their potencies for the competition with the (+)-[3H]PN 200-110 binding to the pig coronary artery.
Effect of the newly synthetized calcium antagonist isopropyl methyl 2-carbamoyloxymethyl-6-methyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5- dicarboxylate on cerebral venous outflow in dogs
Arzneimittelforschung 1989 Jun;39(6):678-81.PMID:2775334doi
The effects of intravenous administration of isopropyl methyl 2-carbamoyloxymethyl-6-methyl-4-(2,3-dichlorophenyl)-1,4-dihydroyridi ne- 3,5-dicarboxylate (NB-818) on mean arterial blood pressure (MBP), heart rate (HR), cerebral blood flow (CBF), cerebral vascular resistance (CVR), arteriovenous oxygen difference (AVO2D), cerebral metabolic rate of oxygen (CMRO2) and blood gases were studied using the method of the cerebral venous outflow in dogs, and compared to those of nicardipine and nimodipine. 1. NB-818, nicardipine and nimodipine (1-10 micrograms/kg) decreased MBP dose-dependently accompanied by a decrease in HR only at doses of 10 micrograms/kg (NB-818) and 3-10 micrograms/kg (nimodipine). 2. NB-818 (1-10 micrograms/kg) increased CBF dose-dependently accompanied by a decrease in CVR. When comparing the potency or duration of action, the action of NB-818 showed a slower onset and was longer-lasting than that of nicardipine or nimodipine. 3. All three drugs (1-10 micrograms/kg) did not significantly affect CMRO2, AVO2D and blood gases (pH, pCO2 and pO2). These results indicate that the increase in CBF with NB-818 is longer in duration than that with nicardipine or nimodipine, and its effect is due to the dilatation of cerebral vessels. In addition, these results suggest that NB-818 is a potent cerebrovasodilator.