1. Previous reports of the effects of alpha 2-adrenoceptor stimulation on gastric secretion are inconsistent because it was not clear whether the compounds were activating alpha 2-adrenoceptors and/or newly described imidazoline receptors. In the present experiments, the effects of moxonidine, an I1-imidazoline receptor agonist and antihypertensive agent, on gastric secretion and on experimental gastric mucosal injury were examined.
2. Moxonidine (0.01, 0.1 and 1.0 mg kg-1, i.p.) potently inhibited basal (non-stimulated) gastric acid secretion in conscious rats with an ED50 of 0.04 mg kg-1. Two hours following administration of the highest dose of moxonidine (1.0 mg kg-1), gastric acid output was completely suppressed. Moxonidine also significantly increased intragastric pH, at the two highest doses.
3. The alpha 2-adrenoceptor agonist, clonidine (0.01, 0.1 and 1.0 mg kg-1, i.p.) decreased basal acid secretion at the lowest dose (37%) and at the highest dose (46%), while the intermediate dose did not affect gastric acid output.
4. In an ethanol-induced model of gastric mucosal injury, moxonidine decreased the length of lesions at the lowest and highest doses (0.01 and 1.0 mg kg-1) as well as the number of the lesions, at the highest dose (1.0 mg kg-1).
5. In pylorus-ligated rats, moxonidine significantly decreased acid secretion (all doses), total secretory volume (1.0 mg kg-1) as well as pepsin output (1.0 mg kg-1).
6. In comparison to clonidine, moxonidine appears to be a more potent anti-secretory and gastric-protective compound. These data indicate a potential role for imidazoline receptor agonists in the management of gastroduodenal diseases associated with hypertension. The relative contribution of the central and peripheral effects of moxonidine to these gastrointestinal actions remains to be determined.

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 the oral dose is absorbed, with negligible effects from food intake or first-pass metabolism, resulting in a bioavailability of up to 88%. The drug is almost entirely excreted by the kidneys, with the majority (50-75%) of mosonidin excreted unchanged. Ultimately, over 90% of the dose is excreted by the kidneys within 24 hours of administration, with only about 1% excreted in feces. The plasma concentration is 1.8 ± 0.4 L/kg. Due to its short half-life, twice-daily dosing is required. However, due to reduced clearance, dose adjustments and close monitoring are necessary for elderly patients and those with renal impairment. Specifically, a single dose can increase drug exposure (AUC) by approximately 50%; in elderly patients and those with moderate renal impairment (glomerular filtration rate (GFR) between 30-60 mL/min), AUC can increase by 85% and clearance can decrease to 52% at steady state.

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Metabolism/Metabolites
Biotransformation of mosonidin is not significant; only 10-20% of mosonidin undergoes oxidation to produce the major metabolites 4,5-dehydromosonidin and guanidine derivatives (through ring-opening of the imidazoline ring). The hypotensive effects of these 4,5-dehydromosonidin and guanidine metabolites are only 1/10 and 1/100 of those of mosonidin, respectively. Oxidation of the methyl (pyrimidine ring) or imidazoline ring of mosonidin produces hydroxymethylmosonidin metabolites or hydroxymosonidin metabolites, respectively. Hydroxymosonidin metabolites can be further oxidized to dihydroxy metabolites or dehydrated to dehydromosonidin metabolites, which can then be further oxidized to N-oxides. In addition to the aforementioned phase I metabolites, phase II metabolism of mosonidin also involves a non-chlorinated cysteine-bound metabolite. However, high concentrations of dehydromosonidin metabolites and hydroxymosonidin metabolites were detected in human urine samples, indicating that the dehydrogenation of the hydroxyl metabolite to form the dehydromosonidin metabolite is the primary metabolic pathway in the human body. The cytochrome P450 responsible for the metabolism of mosonidin in the human body has not yet been identified. Finally, the parent compound mosonidin was observed to be the most abundant component in different biological matrices of urine excretion samples, confirming that metabolism plays only a minor role in the elimination of mosonidin from the human body.
Biological Half-Life
The plasma elimination half-life is 2.2–2.3 hours, and the renal elimination half-life is 2.6–2.8 hours.

Protein Binding
Approximately 10% of mosonic acid binds 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 belonging to the pyrimidine class of drugs. Mosonidin is a new-generation centrally acting antihypertensive drug approved for the treatment of mild to moderate essential hypertension. It is considered effective when other medications, such as thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers, are unsuitable or ineffective. Furthermore, studies have shown that mosonidin has a blood pressure-independent benefit for insulin resistance syndrome. Drug Indications: For the treatment of mild to moderate essential hypertension. As monotherapy, its efficacy is comparable to most first-line antihypertensive drugs. FDA Label: Treatment of hypertension. Mechanism of Action: Stimulation of central α2-adrenergic receptors inhibits sympathetic adrenal function, thereby lowering blood pressure. Further research has revealed that sympathetic adrenal activity can also be inhibited through a second pathway involving a newly discovered imidazoline-specific drug target. Specifically, mosonidin binds to imidazoline receptor subtype 1 (I1) in the respiratory syncytial body (RSV) and to a small extent to α2-adrenergic receptors, thereby reducing sympathetic nerve activity, decreasing systemic vascular resistance, and consequently lowering arterial blood pressure. Furthermore, since α2-adrenergic receptors are considered the primary molecular targets for the most common side effects of centrally acting antihypertensive drugs, such as sedation and dry mouth, mosonidin differs from other centrally acting antihypertensive drugs in that it has a lower affinity for central α2-adrenergic receptors compared to the aforementioned I1-imidazoline receptor.

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Pharmacodynamics
An antihypertensive drug acting on the central nervous system (CNS), specifically involving interactions with I1-imidazoline and α2-adrenergic receptors in the anterior ventrolateral medulla oblongata (RSV).

C9H12CLN5O

241.68

241.073

75438-57-2

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

4810

White to off-white solid powder

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

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)

Solubility in Formulation 1: ≥ 2 mg/mL (8.28 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2 mg/mL (8.28 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2 mg/mL (8.28 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)