I1 imidazoline receptor (selective agonist, I1:α2 affinity ratio = 40:1 to 70:1) [1]; α2-adrenoceptor [1].

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.
In anesthetized rabbits, the dose of Moxonidine required intravenously is 30-fold higher than that required intracisternally to produce the same fall in blood pressure [1].
In cats, injection of a single dose of Moxonidine into the vertebral artery produced a considerably greater hypotensive effect than the same dose injected into the femoral artery [1].
Moxonidine has no hypotensive effect in pithed rats and in cats following spinal cord transection [1].
Micro-injection of Moxonidine into the rostral ventrolateral medulla (RVLM) in rats produces profound falls in blood pressure [1].
Following intravenous administration of Moxonidine in spontaneously hypertensive rats, injection of the I1 receptor antagonist efaroxan into the RVLM blocks the hypotensive action of Moxonidine [1].
In rats, Moxonidine potently reduces gastric acid and pepsin production and protects against gastric mucosal injury [1].
In rats, Moxonidine reduces ischemia-induced cardiac arrhythmias and dose-dependently increases the number of rats that survive without developing arrhythmias following coronary artery ligation [1].
In rats, Moxonidine increases sodium excretion and induces diuresis; intrarenal injection induces natriuresis [1].
In obese spontaneously hypertensive rats (a model for human syndrome X), Moxonidine significantly reduces body weight, cholesterol, triglycerides and insulin levels [1].
Moxonidine lowers plasma renin activity by reducing sympathetic tone [1].

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.

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In anesthetized rabbits, the dose required intravenously vs. intracisternally to produce the same fall in blood pressure was compared (30-fold difference) [1].
In cats, Moxonidine was injected into the vertebral artery or femoral artery, and hypotensive effects were compared [1].
Pithed rats and cats with spinal cord transection were used to assess the central site of action [1].
Micro-injection of Moxonidine into the rostral ventrolateral medulla (RVLM) in rats was performed to measure blood pressure changes [1].
In spontaneously hypertensive rats, intravenous Moxonidine was administered, followed by injection of the I1 antagonist efaroxan into the RVLM to block the hypotensive action [1].
In rats, gastric secretion and mucosal injury studies were conducted with Moxonidine [1].
In rats, coronary artery ligation was performed to induce arrhythmias, and Moxonidine was administered to assess anti-arrhythmic effects [1].
Intrarenal injection of Moxonidine in rats was used to study natriuresis [1].
Obese spontaneously hypertensive rats were treated with Moxonidine to assess metabolic parameters [1].

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.

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After oral administration, Moxonidine is rapidly and almost completely absorbed from the gastrointestinal tract, with absolute bioavailability estimated at 88%; absorption is unaffected by food [1].
In 18 healthy male volunteers receiving an oral dose of 200 μg Moxonidine, peak plasma concentration (Cmax) was 1.50 ± 0.65 ng/ml, time to maximum plasma concentration (Tmax) was 0.56 ± 0.28 hours, and half-life (t1/2) was 1.98 ± 0.68 hours [1].
The volume of distribution after intravenous administration was calculated to be 1.83 L/kg, with 0.44 L/kg apportioned to the central compartment [1].
A 14C radiolabeled study showed modest metabolism; two metabolites were identified (4,5-dehydromoxonidine and a guanidine derivative), but 85–90% of the drug is excreted unchanged renally, and metabolites have less than 10% of the antihypertensive potency of the parent drug [1].
Total clearance following oral administration was calculated at 12.8 ± 2.5 ml/min/kg [1].
Multiple oral dosing with 200 μg Moxonidine twice daily does not alter pharmacokinetics, and drug accumulation does not occur [1].
In renal impairment, the excretion half-life, Cmax and area under the curve (AUC) all rise significantly, levels being inversely proportional to glomerular filtration rate [1].
In elderly patients, Tmax and AUC rise, and total clearance falls, although renal clearance remains unchanged; no drug accumulation is observed if renal function is normal [1].
Only about 7% of circulating Moxonidine is plasma protein-bound [1].
No drug-drug interaction has been demonstrated between Moxonidine and digoxin, hydrochlorothiazide or glibenclamide [1].

Protein Binding
Approximately 10% of mosonic acid binds to plasma proteins.

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Dry mouth occurs in around 10% of patients treated with Moxonidine; sedation is less common than with older centrally-acting drugs [1].
In a double-blind study comparing equipotent doses of Moxonidine and clonidine, 30% of patients experienced side effects with Moxonidine compared to 53% with clonidine; dry mouth and oedema were significantly less common with Moxonidine, but no statistically significant reduction in sedation was reported [1].
Rebound (overshoot) hypertension has not been observed after abrupt withdrawal of Moxonidine in animal models or humans, in contrast to clonidine [1].
In a total of 970 patients who received Moxonidine in controlled clinical trials, nine serious adverse events were documented; six were felt to be unrelated to the drug and three were thought related (cardiac failure, unstable angina and syncope) [1].
Standard toxicology studies suggest that Moxonidine is devoid of any mutagenic, carcinogenic or teratogenic effects [1].
Moxonidine is excreted in breast milk and is contraindicated in pregnancy or breast-feeding [1].
The data sheet recommends avoiding Moxonidine in patients with Raynaud's phenomenon, peripheral vascular disease, cardiac conduction defects, unstable angina and severe cardiac failure; it must be used with care in moderate renal impairment [1].

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).

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Moxonidine reduces blood pressure by an action in the rostral ventrolateral medulla (RVLM), reducing sympathetic outflow and lowering peripheral vascular resistance; hemodynamic studies confirm that BP reduction is not accompanied by any significant change in heart rate or cardiac output [1].
Moxonidine reduces plasma levels of adrenaline and noradrenaline, and plasma renin activity [1].
The anti-arrhythmic effect is most likely a result of reduced sympathetic outflow as Moxonidine does not directly alter cardiac refractoriness or ECG intervals [1].
In healthy human volunteers, no effect of Moxonidine on renal excretory function or renal hemodynamics was revealed [1].
Short term studies in humans suggest Moxonidine is metabolically ‘neutral’ with no effect on glucose, cholesterol or triglyceride levels after 1 year of treatment [1].
Clinical studies: In an open multicentre study (141 patients), Moxonidine (starting 200 μg once daily, up to 800 μg) reduced BP from 170±13.6/103.2±6.3 mmHg to 147.5±12.1/88.4±5.9 mmHg over 12 months; 58.2% maintained on 200 μg/day, 37.6% on 400 μg/day [1].
In a double-blind placebo-controlled study, Moxonidine 200 μg twice daily and 400 μg once daily significantly reduced 24-h systolic and diastolic BP with no significant change in heart rate [1].
Moxonidine reduced mean interventricular septal thickness from 22.5 mm to 19.1 mm over 6 months in patients with left ventricular hypertrophy (cardiac magnetic resonance imaging) [1].
Comparative studies: Moxonidine 200 μg twice daily vs captopril 25 mg twice daily showed similar BP reductions (24-h ambulatory BP) [1]; vs enalapril 5 mg once daily (doubled after 2 weeks) showed response rates 60% vs 66%; trough:peak ratio 0.73 [1]; vs atenolol 50 mg once daily showed similar BP reductions [1]; vs sustained-release nifedipine 20-40 mg once daily showed response 81.5% vs 90.7% [1]; combination with hydrochlorothiazide 25 mg once daily showed mean BP reduction 27±16/16±7.9 mmHg, superior to either alone [1]; vs prazosin 1-3 mg/day: similar BP reduction but once-daily dosing for Moxonidine vs three times daily for prazosin, fewer adverse effects [1]; vs clonidine 200-300 μg/day: both equi-effective, but adverse effects less frequent with Moxonidine (6 vs 17 patients) [1].
Moxonidine is the first UK-licensed member of the I1 imidazoline receptor agonist class of centrally-acting antihypertensive agents. It may be used as first-line treatment for uncomplicated essential hypertension, or in patients intolerant of or unresponsive to other classes [1].

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.)