Metoprine
(Synonyms: 氯苯氨啶,BW 197U) 目录号 : GC61058
Metoprine(BW197U)是一种有效的组胺N-甲基转移酶(HMT)抑制剂。Metoprine是一种二氨基嘧啶衍生物，可以透过血脑屏障，并通过抑制HMT增加脑组胺水平。Metoprine是一种抗叶酸(antifolate)和抗肿瘤药。
Cas No.:7761-45-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Metoprine (BW 197U) is a potent histamine N-methyltransferase (HMT) inhibitor. Metoprine, a diaminopyrimidine derivative, can cross the blood-brain barrier and increase brain histamine levels by inhibiting HMT[1][2]. Metoprine is an antifolate and antitumor agent[3].
Metoprine (BW 197U; 2-10 mg/kg; IP) ameliorates the memory deficits induced by nucleus basalis magnocellularis (NBM) lesions in a dose-dependent manner[2].Intraperitoneal administration of Metoprine produces various behavioral effects, including decreases in food intake and increases in water consumption[1]. Animal Model: Male Sprague-dawley rats (200-280g)[2]
[1]. Junichi Kitanaka, et al. Brain Histamine N-Methyltransferase As a Possible Target of Treatment for Methamphetamine Overdose. Drug Target Insights. 2016 Mar 2;10:1-7. [2]. Zhong Chen, et al. Effects of brain histamine on memory deficit induced by nucleus basalis-lesion in rats. Acta Pharmacol Sin. 2002 Jan;23(1):66-70. [3]. John R Horton, et al. Structural basis for inhibition of histamine N-methyltransferase by diverse drugs. J Mol Biol. 2005 Oct 21;353(2):334-344.
| Cas No. | 7761-45-7 | SDF | |
| 别名 | 氯苯氨啶,BW 197U | ||
| Canonical SMILES | CC1=C(C(N)=NC(N)=N1)C2=CC=C(C(Cl)=C2)Cl | ||
| 分子式 | C11H10Cl2N4 | 分子量 | 269.13 |
| 溶解度 | 储存条件 | Store at -20°C | |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.7157 mL | 18.5784 mL | 37.1568 mL |
| 5 mM | 0.7431 mL | 3.7157 mL | 7.4314 mL |
| 10 mM | 0.3716 mL | 1.8578 mL | 3.7157 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Metoprine, a histamine N-methyltransferase inhibitor, attenuates methamphetamine-induced hyperlocomotion via activation of histaminergic neurotransmission in mice
Pharmacol Biochem Behav 2021 Oct;209:173257.PMID:34418452DOI:10.1016/j.pbb.2021.173257.
Metoprine increases the content of histamine in brain by inhibiting histamine N-methyltransferase (HMT), a centrally acting histamine degrading enzyme. We present data demonstrating that pretreatment with Metoprine attenuates the hyperlocomotive effects of METH in mice using a multi-configuration behavior apparatus designed to monitor four behavioral outcomes [horizontal locomotion, appetitive behavior (food access), and food and water intake]. Metoprine pretreatment itself induced hyperlocomotion in mice challenged with saline during the large part of light phase. The trend was also observed during the following dark phase. This is the first report that Metoprine has a long-lasting locomotor stimulating property. Similarly, in a tail suspension test, a single injection of Metoprine significantly reduced total time of immobility in mice, consistent with the idea that Metoprine possesses motor stimulating properties. Metoprine pretreatment did not affect other aspects of behavior. Metoprine did not affect the appetitive and drinking behavior while exerted an effect on stereotypy. No stereotyped behavior was observed in mice pretreated with vehicle followed by METH, while stereotyped sniffing was observed in mice pretreated with Metoprine followed by METH. The Metoprine pretreatment attenuated METH-induced hyperlocomotion during the first 2 h of light phase, suggesting that metoprine-induced locomotor stimulating property might be different from that of METH. The hypothalamic content of histamine (but not its brain metabolite) was increased after Metoprine or METH administration. Both METH and Metoprine reduced dopamine and histamine turnover in the striatum and the nucleus accumbens and the hypothalamus, respectively, and there is a significant Metoprine pretreatment x METH challenge interaction in the histamine turnover. It is likely that Metoprine may attenuate METH-induced hyperlocomotion via activation of histaminergic neurotransmission. Metoprine also might induce a long-lasting locomotor stimulating effect via a putative mechanism different from that whereby METH induces the locomotor stimulating effect.
Metoprine induced behavioral modifications and brain regional histamine increase in WAG/Rij and Wistar rats
Epilepsy Res 2012 Aug;101(1-2):148-56.PMID:22503455DOI:10.1016/j.eplepsyres.2012.03.016.
The effects of Metoprine, an inhibitor of histamine N-methyltransferase, on open field activity and brain regional histamine (HA) content were examined in rats with mixed, absence and audiogenic, epilepsy (WAG/Rij-AGS), rats with audiogenic epilepsy (Wistar-AGS) and in non-epileptic control rats (Wistar-nAGS). HA content was increased by Metoprine (20mg/kg, i.p.) in the cortex, striatum, thalamus, hypothalamus and hippocampus of the rats from all three tested groups. However, WAG/Rij rats showed a lower rate of metoprine-induced HA accumulation in the striatum and thalamus than Wistar rats. For the open field test, the main effect of Metoprine (20mg/kg, i.p.) was a general increase of locomotor activity although distinctive features, such as hyperlocomotion and exaggerated sniffing, were characteristic for the epileptic rats (WAG/Rij-AGS and Wistar-AGS, respectively). Individual rats from all the groups showed stereotyped behavior of shuttle type and head bobbing. Electroencephalographic data obtained in WAG/Rij-AGS rats confirmed that metoprine-induced behavioral activation was accompanied by suppression of spike-wave discharges, the main hallmark of absence seizures. Taken together, these results show that inhibition of the histamine catabolism may induce motor activation of particular patterns in epileptic rats and provoke stereotyped behavior.
Metoprine-induced thirst and diuresis in Wistar rats
Acta Physiol Scand 1999 Mar;165(3):325-33.PMID:10192183DOI:10.1046/j.1365-201X.1999.00513.x.
In the present study, the renal responses to Metoprine, a histamine-N-methyltransferase inhibitor, were studied in conscious rats. Metoprine (10-20 mg kg(-1)) or vehicle were administered i.p. to male Wistar rats and the effects were followed for the subsequent 24 h. It was found that as early as 3 h after the drug administration Metoprine 20 mg kg(-1) had increased water consumption and urine flow approximately 6-8-fold. The treatment decreased urine osmolality and increased free water clearance, but caused no change in plasma renin activity or plasma vasopressin concentration. In addition, a metoprine-induced elevation in the systolic blood pressure was observed during the first few hours of the experiment. During the nocturnal period of the study, glomerular filtration rate and the excretion of electrolytes did not increase in metoprine-treated rats as they did in control rats. A decrease in the release of atrial natriuretic peptide was also found. The present results show that inhibition of histamine catabolism by Metoprine causes massive changes in renal functions. It seems to promote water excretion by the kidneys but, on the other hand, to reduce the excretion of electrolytes. Although the exact mechanisms, especially the role of increased blood pressure and nocturnal suppression of atrial natriuretic peptide, require further clarification, the present data suggest that renin-angiotensin system and vasopressin were not involved in these renal responses to Metoprine.
Kinetics of Metoprine, a lipid-soluble antifolate
Br J Clin Pharmacol 1981 Nov;12(5):675-80.PMID:7332733DOI:10.1111/j.1365-2125.1981.tb01288.x.
1 Using a dihydrofolate reductase inhibition assay, we have conducted either pharmacokinetic studies in six patients receiving Metoprine. 2 The serum level v time-curve for Metoprine equivalents was irregular; first-order elimination was not observed during the study period of 0--120 h. A model-independent analysis was therefore performed, employing the area under the curve during the first 120 h (AUC). 3 At an oral dose of 65 mg/m2 without leucovorin, a peak level of 0.6 microgram/ml and an AUC of 52 micrograms ml-1 h produced significant leukopenia and thrombocytopenia. 4 At doses ranging from 100 mg/m2 to 175 mg/m2 orally, with leucovorin administration 40 mg/m2 intravenously at 24 and 96 h, haematologic toxicity was seen in only 1 patient who received 175 mg/m2. This patient also had the highest peak serum level (2.8 micrograms/ml) and AUC (228 micrograms ml-1 h). 5 One partial response and one minor regression were observed in the studied patients; these two patients had the 175 mg/m2 dose, highest peak levels (2.4 and 2.8 micrograms/ml) and highest AUCs (197 and 228 micrograms ml-1 h). The other patients had lower peak levels and AUCs and had neither therapeutic response nor hematologic toxicity. 6 The AUC and peak serum levels were linearly related to each other (P less than 0.001). 7 Total urinary excretion of dihydrofolate reductase inhibitors (as Metoprine equivalents) in the first 120 h ranged from 5 to 17% of the administered dose.
Metoprine, an inhibitor of histamine N-methyltransferase but not catechol-O-methyltransferase, suppresses feeding in sated and in food deprived rats
Methods Find Exp Clin Pharmacol 1995 Jan-Feb;17(1):47-52.PMID:7542717doi
Metoprine is a histamine N-methyltransferase (HMT) inhibitor often used to elevate endogenous histamine (HA) levels when studying the role of brain HA. Since central histaminergic systems may be involved in the regulation of feeding, the effect of Metoprine on food intake was studied in sated and in food deprived rats. The treatment caused a dose-dependent decrease in food intake in sated rats. It also suppressed deprivation-induced feeding. To clarify the specificity of the treatment, the effect of Metoprine on another methylating enzyme, catechol-O-methyltransferase (COMT), was examined indirectly by examining the ratio of the non-methylated dopamine metabolite, dihydroxyphenylacetic acid (DOPAC) to that of its methylated product homovanillic acid (HVA). The dopamine metabolites did not change in a manner consistent with COMT inhibition, but instead a transient decrease in DOPAC levels was observed. However, the suppression of feeding is considered to be related to the metoprine-induced inhibition of brain HA catabolism and not with the changes in dopaminergic systems. Metoprine had no effect on brain concentration of serotonin (5-HT) or its metabolite 5-hydroxyindoleacetic acid (5-HIAA). The results provide further support for the role of brain HA in the control of feeding behavior.