1. 先前关于 α 2-肾上腺素受体刺激对胃液分泌的影响的报道不一致，因为不清楚这些化合物是激活 α 2-肾上腺素受体还是新近描述的咪唑啉受体。在本实验中，研究了 I1-咪唑啉受体激动剂和抗高血压药物 莫索尼定 对胃液分泌和实验性胃粘膜损伤的影响。
2. 莫索尼定 (0.01、0.1 和 1.0 mg kg-1，腹腔注射) 可有效抑制清醒大鼠的基础（非刺激）胃酸分泌，ED50 为 0.04 mg kg-1。在给予最高剂量 莫索尼定 (1.0 mg kg-1) 两小时后，胃酸分泌完全被抑制。 莫索尼定在两个最高剂量下也显著升高了胃内 pH 值。
3. α2-肾上腺素能受体激动剂可乐定 (0.01、0.1 和 1.0 mg kg-1，腹腔注射) 在最低剂量 (37%) 和最高剂量 (46%) 下降低了基础酸分泌，而中间剂量不影响胃酸输出。
4.在乙醇诱发的胃粘膜损伤模型中，莫索尼定在最低和最高剂量（0.01 和 1.0 mg kg-1）下减少了病变长度，在最高剂量（1.0 mg kg-1）下减少了病变数量。
5. 在幽门结扎大鼠中，莫索尼定显著降低酸分泌（所有剂量）、总分泌量（1.0 mg kg-1）以及胃蛋白酶输出（1.0 mg kg-1）。
6. 与可乐定相比，莫索尼定似乎是一种更有效的抗分泌和胃保护化合物。这些数据表明咪唑啉受体激动剂在治疗与高血压相关的胃十二指肠疾病方面具有潜在作用。 莫索尼定的中枢和外周作用对这些胃肠道作用的相对贡献仍有待确定。

胃酸分泌
雄性 Sprague-Dawley 大鼠（研究开始时体重为 180 ± 10g）植入慢性留置胃插管，如前所述（Pare 等，1977）。经过 14 天的恢复期后，所有插管均牢固连接，未产生不良影响。分泌测试以 3 小时为一个阶段，顺序如下：载体（盐水 1.0 ml kg-'）、莫索尼定 0.01 mg kg-'、0.1 mg kg-'。1.0 mg kg-' 腹腔注射，再次注入载体。每个阶段间隔 96 小时。在每个分泌测试阶段，基线收集后注射（腹腔注射）载体或莫索尼定，随后进行两次治疗后收集。因此，每只动物作为自己的对照，所有药物治疗前都有一个 1 小时的基线收集期，在此期间不进行注射。所有药物治疗均在注射载体之前和之后进行。记录分泌量，并使用 Mettler DL-21 自动滴定仪用 0.01 M NaOH 将每个样品的等分试样滴定至 pH 7.0。结果以 limol h-' 表示。为了进行比较，其他动物按上述方法准备，但按上述方法腹腔注射载体和可乐定，剂量为 0.01、0.1 和 1.0mgkg-'。
乙醇引起的胃粘膜损伤
将大鼠（每组 n = 5）随机分配到治疗组。在通过管饲法口服 1.0 ml 75% (v/v) 乙醇（加拿大工业酒精和化学品有限公司，加拿大安大略省科比维尔）之前，24 小时内禁食但不禁水（Robert 等人，1979 年）。在注射乙醇前 5 分钟腹腔注射剂量为 0.01、0.1 或 1.0mg kg-' 的载体或莫索尼定。在注射乙醇和药物后，将大鼠放回单独的笼子中，不给食物或水，持续 2 小时，然后通过颈椎脱位杀死大鼠。取出胃，翻出，清洗并固定在 10% (v/v) 缓冲福尔马林中，由治疗“盲法”观察员在解剖显微镜下用目镜测微计测定胃腺粘膜损伤的数量和累积长度（以毫米为单位）。

Gastric acid secretion
Male Sprague-Dawley rats (180 ± 1Og at the start of the study) were implanted with chronic indwelling gastric cannulae as described previously (Pare et al., 1977). After a 14-day recovery period, all cannulae remained firmly attached and produced no untoward effects. Secretory testing in sessions of 3 h occurred in the following sequence: vehicle (saline 1.0 ml kg-'), moxonidine 0.01 mg kg-', 0.1 mg kg-'. 1.0 mg kg-' i.p. and vehicle again. Each of these sessions was separated by a 96 h period. Within each secretory testing session, a baseline collection was followed by the injection (i.p.) of the vehicle or moxonidine and two subsequent post treatment collections. Thus, each animal served as its own control and all drug treatments were preceded by a 1 h baseline collection period in which no injection occurred. All drug treatments were both preceded and followed by vehicle injections. The volume of secretion was recorded and aliquots of each sample were titrated to pH 7.0 with 0.01 M NaOH in a Mettler DL-21 autotitrator. The results are expressed as limol h-'. For purposes of comparison, other animals were prepared as described above, but given vehicle and clonidine at doses of 0.01, 0.1 and 1.0mgkg-' i.p. as described as above.
Ethanol-induced gastric mucosal injury
Rats (n = 5 per group) were randomly assigned to treatment conditions. They were deprived of food, but not water, for 24 h prior to being given 1.0 ml of 75% (v/v) ethyl alcohol (Canadian Industrial Alcohols and Chemicals Ltd., Corbyville, Ontario, Canada) p.o. by gavage (Robert et al., 1979). Vehicle or moxonidine at doses of 0.01, 0.1, or 1.0mg kg-' was given i.p. 5 min prior to ethanol. Following ethanol and drug treatment, rats were returned to individual cages without food or water for 2 h, after which time they were killed by cervical dislocation. The stomachs were removed, everted, washed and fixed in 10% (v/v) buffered formalin and the number and cumulative length (in millimeters) of gastric glandular mucosal injury determined under a dissecting microscope with an ocular micrometer by a treatment-'blinded' observer.

Absorption, Distribution and Excretion
90% of an oral dose is absorbed with negligible interference from food intake or first pass metabolism, resulting in a high bioavailability of 88%.
Elimination is nearly entirely via the kidneys with a majority (50 -75%) of overall moxonidine being eliminated unchanged through renal excretion. Ultimately, more than 90% of a dose is eliminated by way of the kidneys within the first 24 hours after administration, with only approximately 1% being eliminiated via faeces.
1.8±0.4L/kg.
Administered twice daily due to short half life. However, lower dosage adjustments and close monitoring is necessary in elderly and renal impairment patients due to reduced clearance. In particular, the exposure AUC can increase by about 50% following a single dose and at steady state in elderly patients and moderately impaired renal function with GFR between 30-60 mL/min can cause AUC increases by 85% and decreases in clearence to 52 %.

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Metabolism / Metabolites
Biotransformation is unimportant with 10-20% of moxonidine undergoing oxidation reactions to the primary 4,5-dehydromoxonidine metabolite and a guanidine derivative by opening of the imidazoline ring. The antihypertensive effects of these 4,5-dehydromoxonidine and guanidine metabolites are only 1/10 and 1/100 the effect of moxonidine. Oxidation on either the methyl group (pyrimidine ring) or on the imidazole ring of moxonidine results in the formation of the hydroxylmethyl moxonidine metabolite or the hydroxy moxonidine metabolite. The hydroxy moxonidine metabolite can be further oxidized to the dihydroxy metabolite or it can lose water to form the dehydrogenated moxonidine metabolite, which itself can be further oxidized to form an N-oxide. Aside from these Phase I metabolites, Phase II metabolism of moxonidine is also evident with the presence of a cysteine conjugate metabolite minus chlorine. Nevertheless, the identification of the hydroxy moxonidine metabolite with a high level of dehydrogenated moxonidine metabolite in human urine samples suggests that dehydrogenation from the hydroxy metabolite to the dehydrogenated moxonidine metabolite represents the primary metabolic pathway in humans. The cytochromes P450 responsible for the metabolism of moxonidine in humans have not yet been determined. Ultimately, the parent moxonidine compound was observed to be the most abundant component in different biological matrices of urinary excretion samples, verifying that metabolism only plays a modest role in the clearance of moxonidine in humans.

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Biological Half-Life
Plasma elimination half life is 2.2 - 2.3 hours while renal elimination half life is 2.6-2.8 hours.

Protein Binding
About 10% of moxonidine is bound to plasma proteins.

J Cardiovasc Pharmacol.2004Feb;43(2):306-11;J Hum Hypertens.1997 Oct;11(10):629-35;Br J Pharmacol.1995 Feb;114(4):751-4.

Moxonidine is an organohalogen compound and a member of pyrimidines.
Moxonidine is a new-generation centrally acting antihypertensive drug approved for the treatment of mild to moderate essential hypertension. It is suggested to be effective in cases where other agents such as thiazides, beta-blockers, ACE inhibitors, and calcium channel blockers are not appropriate or irresponsive. As well, moxonidine has been shown to present blood pressure-independent beneficial effects on insulin resistance syndrome.

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Drug Indication
For the treatment of mild to moderate essential or primary hypertension. Effective as most first-line antihypertensives when used as monotherapy.
FDA Label
Treatment of hypertension

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Mechanism of Action
Stimulation of central alpha 2-adrenergic receptors is associated with sympathoadrenal suppression and subsequent reduction of blood pressure. As this class was further explored it was discovered that sympathoadrenal activity can also be suppressed by a second pathway with a newly discovered drug target specific to imidazolines. Specifically, moxonidine binds the imidazoline receptor subtype 1 (I1) and to a lesser extent αlpha-2-adrenoreceptors in the RSV causing a reduction of sympathetic activity, reducing systemic vascular resistance and thus arterial blood pressure. Moreover, since alpha-2-adrenergic receptors are considered the primary molecular target that facilitates the most common side effects of sedation and dry mouth that are elicited by most centrally acting antihypertensives, moxonidine differs from these other centrally acting antihypertensives by demonstrating only low affinity for central alpha-2-adrenoceptors compared to the aforementioned I1-imidazoline receptors.

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Pharmacodynamics
Antihypertensive agent whose site of action is the Central Nervous System (CNS), specifically involving interactions with I1- imidazoline and alpha-2-adrenergic rececptors within the rostral ventrolateral medulla (RSV).

C9H12CLN5O

241.68

241.073

75438-57-2

Moxonidine hydrochloride;75536-04-8;Moxonidine-d4;1794811-52-1

4810

Typically exists as solid at room temperature

1.5±0.1 g/cm3

364.7±52.0 °C at 760 mmHg

40-43 °C(lit.)

174.3±30.7 °C

0.0±0.8 mmHg at 25°C

1.681

0.84

71.43

2

4

3

16

275

0

CC1=NC(OC)=C(NC2=NCCN2)C(Cl)=N1

WPNJAUFVNXKLIM-UHFFFAOYSA-N

InChI=1S/C9H12ClN5O/c1-5-13-7(10)6(8(14-5)16-2)15-9-11-3-4-12-9/h3-4H2,1-2H3,(H2,11,12,15)

4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methylpyrimidin-5-amine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2 mg/mL (8.28 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.0 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2 mg/mL (8.28 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.0mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2 mg/mL (8.28 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。