Microbial Metabolite; Endogenous Metabolite
The drug acts locally in the stomach rather than through a single defined receptor target. The effects are mediated through: (1) activation of vagus nerve via L-glutamate sensing in the gastric mucosa, likely involving glutamate receptors such as metabotropic glutamate receptors (mGluR1, mGluR4), umami taste receptor T1R1/T1R3, and calcium-sensing receptor; (2) nitric oxide (NO) production via nitric oxide synthase (NOS) using L-arginine as substrate. No IC50, Ki, EC50, or DC50 values are reported for specific targets. [1]

In rats, oral administration of 10-30 mg/kg of L-arginine L-glutamic acid dose-dependently increases stomach emptying. The vagus nerve must be activated for this action to occur. Additionally, intragastric L-arginine L-glutamic acid (3–30 mg/kg) improves gastric adaptive relaxation in rats in a dose-dependent manner.
In normal rats, ArgGlu (0.3-30 mg/kg p.o.) dose-dependently promoted gastric emptying of a liquid meal, with significant effects at 10 and 30 mg/kg; the effect was comparable to that of mosapride (0.3-3 mg/kg p.o.). [1]
Intravenous ArgGlu (10 mg/kg) had no effect on gastric emptying, indicating a local gastric site of action. [1]
Gastric vagotomy completely abolished the promoting effect of ArgGlu (10 mg/kg) on gastric emptying, demonstrating dependence on vagus nerve activation. [1]
ArgGlu (1-30 mg/kg intragastrically) dose-dependently enhanced adaptive relaxation of the stomach in anesthetized rats, with significant effects at 3, 10, and 30 mg/kg. [1]
The enhancing effect of ArgGlu (10 mg/kg) on gastric adaptive relaxation was resistant to acute vagotomy but was completely inhibited by pretreatment with L-NAME (20 mg/kg i.v.), a NOS inhibitor, indicating mediation by NO production. [1]
L-Glutamate (1-10 mg/kg p.o.) promoted gastric emptying in a dose-dependent manner (significant at 10 mg/kg), whereas L-arginine had no effect on gastric emptying. [1]
ArgGlu and L-arginine (6 mM intragastrically) significantly enhanced gastric adaptive relaxation in rats, whereas L-glutamate had no effect. [1]
In conscious dogs, intragastric infusion of ArgGlu (6 or 60 mM) significantly increased gastric volume (reduced gastric tone), with effects comparable to sumatriptan (1-3 mg/kg s.c.). [1]
ArgGlu (30 mg/kg p.o.) significantly reduced the half gastric emptying time (T1/2) in clonidine-induced delayed gastric emptying of solids in dogs (from 305.1 min to 278.9 min), with efficacy comparable to cisapride (3 mg/kg p.o., 304.6 min to 275.9 min). [1]

mino acids are not only constituents of proteins, but also have multiple physiologic functions. Recent findings have revealed that ingested amino acids either activate luminal receptors or are metabolized, causing physiologic reactions in the gastrointestinal (GI) tract. We examined the effect of oral L-arginine L-glutamate (ArgGlu), a pharmaceutical amino acid salt used i.v. for the treatment of hyperammonemia, on gastric motor function in rats and dogs. Gastric emptying was determined using phenol red and 13C-breath test methods, whereas gastric relaxation was determined using the barostat method. ArgGlu (10-30 mg/kg, p.o.) dose-dependently promoted gastric emptying in rats. This effect was dependent on vagus nerve activation and comparable to that of the prokinetic mosapride. Intragastric ArgGlu (3-30 mg/kg intragastrically) also dose-dependently enhanced adaptive relaxation of rat stomachs, which was negated not by vagotomy of gastric branches, but by pretreatment with N omega-nitro-L-arginine methyl ester (20 mg/kg i.v.), a nitric oxide synthase inhibitor. Its relaxing effect on the stomach was also confirmed in dogs and was equally as efficacious as treatment with sumatriptan (1-3 mg/kg s.c.). ArgGlu (30 mg/kg p.o.) significantly reduced the half gastric emptying time in clonidine-induced delayed gastric emptying of solids in dogs, and its effect was comparable to that of cisapride (3 mg/kg p.o.). This study demonstrated that the pharmaceutical ingredient ArgGlu, currently used i.v., enhanced gastric motor function when administered orally, suggesting that it could be a new oral medicine indicated for treatment of upper GI hypofunction or dysfunction like functional dyspepsia.[1]

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Rat gastric emptying: Adult male Sprague-Dawley rats (6-7 weeks old) were used. The liquid meal consisted of 10% w/v casein Na and phenol red (50 mg/100 mL) in purified water, administered intragastrically (1.5 mL) to freely fed rats. ArgGlu was dissolved in the liquid meal and administered simultaneously. Mosapride (3 mg/kg) was suspended in 0.5% carboxymethyl cellulose and administered intragastrically 1 hour before the meal. Sixty minutes after meal administration, rats were euthanized by CO2 inhalation. The stomach was isolated, placed in 0.1 N NaOH, and homogenized. After settling, supernatant was mixed with acetonitrile and centrifuged; absorbance was read at 560 nm. Gastric emptying percentage was calculated as (1 - absorbance of test sample/absorbance of standard) × 100. [1]
Vagotomy: Gastric branches of ventral and dorsal vagal trunk were transected under microscope in fasted 5-week-old rats under ketamine (75 mg/kg i.p.) and xylazine (5 mg/kg i.p.) anesthesia. Sham vagotomy involved laparotomy without transection. Rats recovered for 10 days before gastric emptying measurements. [1]
Vagus nerve recording: Male Sprague-Dawley rats (250-330 g) were fasted 18 hours and anesthetized with urethane (1 g/kg i.p.). A polyethylene catheter was inserted into the forestomach for intragastric infusion. Fine vagal filaments from the left gastric branch were dissected and placed on a silver hook-recording electrode. Signals were amplified 10,000×, filtered (150 Hz to 1 KHz), and acquired via PowerLab interface. ArgGlu (2-20 mM, 3 mL) or distilled water was injected intragastrically at 3 mL/min. Mosapride (1 mg/kg i.v.) and acotiamide (10 mg/kg i.v.) were also tested. Nerve activity was analyzed as spikes per second over 15-minute periods. For perfusion experiments, 6 mM ArgGlu was perfused at 3 mL/min for 10 minutes, then switched to 6 mM NaCl. [1]
Rat adaptive relaxation: Male Sprague-Dawley rats (7-8 weeks old) were fasted 16-24 hours and anesthetized with pentobarbital (50 mg/kg i.p.). An intragastric balloon and cannula were inserted through the duodenum into the forestomach. Intragastric pressure and volume were measured with an electronic barostat; pressure was increased stepwise by 2 mmHg to 10 mmHg. Adaptive relaxation was evaluated as intragastric volume at 10 mmHg. ArgGlu (1-30 mg/kg) was administered intragastrically 60 minutes before measurement. L-NAME (20 mg/kg i.v.) was administered 50 minutes after test solution. Vagotomy was performed immediately before treatment. [1]
Canine gastric tone: Female beagles (10-12 kg) were surgically prepared with a gastric cannula 7 cm proximal to the pylorus under thiopental (25 mg/kg i.v.) and halothane (1.0%) anesthesia. A polyethylene bag was inserted into the proximal stomach through the cannula for barostat measurement at 2 mmHg above minimal distending pressure. ArgGlu (0.6-60 mM) was infused intragastrically at 2 mL/min for 25 minutes. Sumatriptan (1-3 mg/kg) was administered subcutaneously. Gastric volume was acquired and averaged every 5 minutes. [1]
Canine delayed gastric emptying: Overnight-fasted dogs were fed 50 g solid dog food containing 20 mg ¹³C-octanoic acid. ArgGlu (30 mg/kg) was dissolved in distilled water (50 mL) and administered orally 20 minutes before the meal. Cisapride (3 mg/kg) was suspended in 0.1% methyl cellulose and administered orally 30 minutes before the meal. Acotiamide (30 mg/kg) was administered orally 30 minutes before the meal. Clonidine (30 μg/kg) was administered subcutaneously 15 minutes before the meal. Gastric emptying was measured by ¹³C-breath test using the BreathID System, and T1/2 (half gastric emptying time) was calculated. [1]

Plasma concentrations of L-glutamate and L-arginine: ArgGlu (10 mg/kg, the dose that significantly promoted gastric emptying) was dissolved in test meal (0.5 mL/kg) and orally administered to rats. Blood was taken from the inferior vena cava under ether anesthesia immediately after (0 min) and at 15, 30, and 60 minutes after administration. Plasma concentrations were measured using LC-ESI-MS/MS. Oral administration of ArgGlu (10 mg/kg) did not increase plasma concentrations of L-glutamate or L-arginine compared with vehicle controls at any time point (0, 15, 30, 60 min). Plasma L-glutamate: vehicle ~106-119 μmol/L; ArgGlu ~114-152 μmol/L. Plasma L-arginine: vehicle ~241-281 μmol/L; ArgGlu ~195-255 μmol/L. [1]
Gastric concentrations: Immediately following intragastric administration of ArgGlu (10 mg/5 mL/kg, approximately 6.2 mmol/L), the concentrations of L-glutamate and L-arginine in the gastric juices were 5.8 and 5.4 mmol/L, respectively (average, N=2). [1]

[1]. L-Arginine L-Glutamate Enhances Gastric Motor Function in Rats and Dogs and Improves Delayed Gastric Emptying in Dogs. J Pharmacol Exp Ther. 2016 Nov;359(2):238-246.

Arginine and glutamic acid are derivatives of glutamic acid.

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L-Arginine L-glutamate (ArgGlu, CAS#: 4320-30-3) is a pharmaceutical amino acid salt approved in Japan as "Argimate® 10% solution for drip intravenous infusion" for the treatment of hyperammonemia. [1]
ArgGlu is a natural amino acid salt of L-arginine and L-glutamate, with molecular weight of 321.33. [1]
The dual mechanism of action involves: (1) L-glutamate activating afferent vagus nerve via mucosal receptors (mGluR1, mGluR4, T1R1/T1R3, CaSR) to promote gastric emptying; (2) L-arginine serving as substrate for NOS to produce NO, which mediates gastric relaxation. [1]
The promoting effect on gastric emptying is mediated through vagus nerve activation, whereas the relaxing effect is mediated through NO production and is independent of vagus nerve reflex. [1]
ArgGlu has a different mechanism from conventional prokinetics (5-HT4 agonists and acetylcholinesterase inhibitors), as mosapride and acotiamide did not activate afferent vagus nerve activity. [1]
The safety of oral administration of ArgGlu has been confirmed at doses up to at least 6 g/day in clinical studies in healthy males, chronic alcoholic patients, patients with episodic encephalopathy, males with erectile dysfunction, and postmenopausal females. [1]
ArgGlu could be a new oral medicine for treatment of upper GI hypofunction or dysfunction like functional dyspepsia (PDS symptoms with delayed gastric emptying and impaired gastric accommodation). [1]

C11H23N5O6

321.33

321.164

C, 41.12; H, 7.21; N, 21.80; O, 29.87

4320-30-3

DL-Arginine;7200-25-1;L-Arginine;74-79-3;L-Arginine butanoate;80407-72-3; 2485-55-4 (caprate); 4320-30-3 (glutamate); 1119-34-2 (HCl)

165268

White to off-white solid powder

409.1ºC at 760 mmHg

191 - 192ºC

201.2ºC

0.516

7

9

9

22

321

2

O([H])C([C@]([H])(C([H])([H])C([H])([H])C([H])([H])/N=C(\N([H])[H])/N([H])[H])N([H])[H])=O.O([H])C([C@]([H])(C([H])([H])C([H])([H])C(=O)O[H])N([H])[H])=O

RVEWUBJVAHOGKA-WOYAITHZSA-N

InChI=1S/C6H14N4O2.C5H9NO4/c7-4(5(11)12)2-1-3-10-6(8)9;6-3(5(9)10)1-2-4(7)8/h4H,1-3,7H2,(H,11,12)(H4,8,9,10);3H,1-2,6H2,(H,7,8)(H,9,10)/t4-;3-/m00/s1

(2S)-2-amino-5-(diaminomethylideneamino)pentanoic acid;(2S)-2-aminopentanedioic acid

Argimate Modumate; Arginine glutamate; NSC-122009; 4320-30-3; L-Arginine L-glutamate; Arginine glutamate; (S)-2-Amino-5-guanidinopentanoic acid compound with (S)-2-aminopentanedioic acid (1:1); L-ARGININE-L-GLUTAMATE; L-Arginine L-glutamate salt; Modumate; L-Arginine, L-glutamate; NSC122009; NCI-C02120; NSC 122009

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)

H2O : ~100 mg/mL (~311.21 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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