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| Targets |
Histamine H2 receptor (H2R). Tiotidine binds to the H2 receptor with high affinity (Ki = 1.2-2.5 nM in radioligand binding assays using [3H]-tiotidine or [125I]-aminopotentidine). It acts as an inverse agonist in cells with constitutive H2 receptor activity (e.g., U-937 histiocytic lymphoma cells), reducing basal cAMP levels by up to 80% (IC50 = 10 nM). It is highly selective for H2 over H1 (Ki > 10 uM), H3 (Ki > 1 uM), and H4 (Ki > 5 uM) receptors. It does not significantly interact with muscarinic, adrenergic, or dopamine receptors.
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| ln Vitro |
The orthochronic effects of histamine are competitively offset by thiitidine, which has an apparent dissociation constant of 30 μM (23-38 μM). The H2-mediated increase in contractility is eliminated by thiitidine, allowing the H2-mediated negative inotropic response to occur unopposed. 2.5 x 10(-7) M thiitidine can lessen the action of histamine on the atrioventricular node, which is seen by an increase in the PR interval and atrioventricular block [2]. In U-937 cells, thiitidine truly functions as an inverse agonist, lowering basal cAMP levels [3].
In vitro, tiotidine (0.1 nM-1 uM) inhibits histamine-stimulated cAMP accumulation in isolated rabbit gastric glands (IC50 = 8 nM) and in guinea pig parietal cells. It also inhibits histamine-induced acid secretion in isolated rabbit gastric glands with an IC50 of 12 nM. In U-937 cells, tiotidine reduces basal (constitutive) cAMP levels by 70% at 100 nM, indicating inverse agonism. It also inhibits IL-8 and TNF-alpha production in LPS-stimulated human monocytes (IC50 = 0.5 uM) and induces apoptosis in certain cancer cell lines (e.g., colon cancer HT-29, IC50 ≈ 30 uM for growth inhibition after 72 h). It has no effect on EGF receptor or HER2 at 10 uM. |
| ln Vivo |
In vivo, tiotidine effectively inhibits gastric acid secretion in animal models and humans. In the rat pylorus-ligated model, oral administration of tiotidine (3-30 mg/kg) reduces gastric acid output by up to 90% (ED50 = 5 mg/kg). In dogs with Heidenhain pouches, tiotidine (0.5 mg/kg IV) inhibits histamine-stimulated acid secretion for 4-6 hours. In humans, a single oral dose of 150 mg reduces overnight gastric acid secretion by 85%. The compound also protects against ethanol-induced gastric mucosal damage in rats (ED50 = 10 mg/kg p.o.). It does not affect blood pressure, heart rate, or gastrointestinal motility at therapeutic doses.
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| Enzyme Assay |
Radioligand binding assay: Membranes prepared from guinea pig brain or from cells expressing human H2 receptors (e.g., CHO-H2) are incubated with 0.5-1 nM [3H]-tiotidine (or [125I]-aminopotentidine) in 50 mM Tris-HCl (pH 7.4) containing 10 mM MgCl2 for 60 min at 25degC. Non-specific binding is defined with 10 uM cimetidine or famotidine. Bound radioligand is collected on GF/B filters presoaked in 0.3% PEI and counted. For competition binding, increasing concentrations of tiotidine (0.01-1000 nM) are added, and Ki is calculated. For inverse agonism, U-937 cells are cultured and treated with tiotidine (0.1-1000 nM) for 30 min, and cAMP is measured by ELISA in the presence of 100 uM IBMX.
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| Cell Assay |
U-937 cells (human histiocytic lymphoma) are grown in RPMI 1640 with 10% FBS. For cAMP assay, cells are resuspended in HBSS containing 0.5 mM IBMX, seeded in 96-well plates (2×10^5 cells/well), and treated with tiotidine (0.1-1000 nM) or vehicle for 30 min at 37degC. After stimulation (if any), cells are lysed, and cAMP is measured using an ELISA kit. For gastric gland acid secretion assay: Rabbit gastric glands are isolated by collagenase digestion. Glands are suspended in HEPES-buffered Ringer solution (pH 7.4) containing 14C-aminopyrine (AP, 0.1 uCi/mL). After 30 min pre-incubation with tiotidine, histamine (100 uM) is added, and the glands are incubated for 60 min. The accumulation of AP (reflecting acid secretion) is measured by liquid scintillation counting. IC50 is determined.
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| Animal Protocol |
Rat pylorus-ligated model: Male Sprague-Dawley rats (200-250 g) are fasted for 24 h with free access to water. Under anesthesia, the pylorus is ligated. Tiotidine (1-30 mg/kg) or vehicle (0.5% methylcellulose) is administered orally 30 min before pylorus ligation. Four hours after ligation, the stomach is removed, and gastric juice is collected. Volume, pH, and acid output (titration to pH 7.0 with 0.1 N NaOH) are measured. ED50 is calculated from the dose-response curve. For the gastric mucosal lesion model, rats receive absolute ethanol (1 mL) orally 30 min after tiotidine (3-30 mg/kg p.o.). One hour later, the stomach is removed, and the lesion area is measured (mm2). Tiotidine significantly reduces lesion area at doses ≥10 mg/kg.
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| ADME/Pharmacokinetics |
Pharmacokinetics in humans: After oral administration of tiotidine (150 mg), Cmax is 0.8-1.2 ug/mL (≈2.5-3.8 uM) at 1-2 hours. The terminal half-life (t½) is approximately 2.5 hours. Oral bioavailability is about 50% (range 40-60%). Plasma protein binding is 15-20% (low). The drug is not extensively metabolized; about 70% of an oral dose is excreted unchanged in urine within 24 hours. In rats, after IV administration (10 mg/kg), t½ is 1.2 h, clearance is 25 mL/min/kg, and Vd is 1.8 L/kg. Food does not significantly affect absorption. Unlike cimetidine, tiotidine does not inhibit CYP450 enzymes (no significant interaction with warfarin or theophylline).
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| Toxicity/Toxicokinetics |
Preclinical toxicity: Oral LD50 in rats is >2000 mg/kg; in mice, >1500 mg/kg. In 13-week repeat-dose studies in dogs (up to 100 mg/kg/day), no significant adverse effects are observed except mild diarrhea at the highest dose. No genotoxicity (Ames test, micronucleus test). In rats, no teratogenic effects are seen at doses up to 500 mg/kg/day. In humans, tiotidine is well tolerated; common adverse effects (incidence 1-5%) include headache, dizziness, constipation, or diarrhea. Rare side effects (<1%) include reversible elevation of liver enzymes, rash, and gynecomastia (with long-term high doses, similar to cimetidine but less frequent). It does not cause anti-androgenic effects (no reduction in sperm count or libido) because it does not bind to androgen receptors.
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| References |
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| Additional Infomation |
1-Cyano-3-[2-[[2-(diaminomethyleneamino)-4-thiazolyl]methylthio]ethyl]-2-methylguanidine is a member of the thiazole class of compounds.
Tiotidine was developed as an alternative to cimetidine and ranitidine for the treatment of peptic ulcer disease, gastroesophageal reflux disease (GERD), and Zollinger-Ellison syndrome. It was approved in some countries (e.g., Italy, Spain, Japan) under brand names such as Tiodine and Gastridin. However, it was never approved by the US FDA. It is now rarely used clinically, having been superseded by more potent H2 antagonists (famotidine) and proton pump inhibitors (omeprazole). Today, tiotidine is primarily used as a research tool for H2 receptor pharmacology, especially in studies of inverse agonism and immune modulation. It is available from chemical suppliers for research use only. The compound is also known as ICI 125211. |
| Molecular Formula |
C10H16N8S2
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|---|---|
| Molecular Weight |
312.41764
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| Exact Mass |
312.094
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| CAS # |
69014-14-8
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| PubChem CID |
50287
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| Appearance |
White to yellow solid powder
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| Density |
1.5g/cm3
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| Boiling Point |
543.6ºC at 760 mmHg
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| Flash Point |
282.5ºC
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| Index of Refraction |
1.728
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| LogP |
1.982
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
20
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| Complexity |
397
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
YDDXVAXDYKBWDX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C10H16N8S2/c1-14-9(16-6-11)15-2-3-19-4-7-5-20-10(17-7)18-8(12)13/h5H,2-4H2,1H3,(H2,14,15,16)(H4,12,13,17,18)
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| Chemical Name |
1-cyano-3-[2-[[2-(diaminomethylideneamino)-1,3-thiazol-4-yl]methylsulfanyl]ethyl]-2-methylguanidine
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~400.10 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.66 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 20.8 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (6.66 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 20.8 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (6.66 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2008 mL | 16.0041 mL | 32.0082 mL | |
| 5 mM | 0.6402 mL | 3.2008 mL | 6.4016 mL | |
| 10 mM | 0.3201 mL | 1.6004 mL | 3.2008 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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