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Caerulein (Caerulein; Cerulein; FI-6934) is a novel, potent and specific decapeptide-based cholecystokinin receptor agonist, it is produced in the skin of Hila caerulea, an Australian amphibian. Caerulein and Cholecytokinin function and are composed similarly. It increases the secretion of pancreatic, biliary, and stomach juices as well as some smooth muscle. It is a diagnostic tool for pancreatic dysfunction and for paralytic ileus.
Physicochemical Properties
| Molecular Formula | C58H73N13O21S2 |
| Molecular Weight | 1352.4047 |
| Exact Mass | 979.374 |
| Elemental Analysis | C, 51.51; H, 5.44; N, 13.46; O, 24.84; S, 4.74 |
| CAS # | 17650-98-5 |
| PubChem CID | 16129675 |
| Sequence | {pGlu}-Gln-Asp-Tyr(SO3H)-Thr-Gly-Trp-Met-Asp-Phe-NH2 |
| SequenceShortening | {pGlu}-QD-Y(SO3H)-TGWMDF-NH2 |
| Appearance | White to off-white solid powder |
| Density | 1.4±0.1 g/cm3 |
| Melting Point | 224-226° (dec) |
| Index of Refraction | 1.632 |
| LogP | 2.46 |
| Hydrogen Bond Donor Count | 17 |
| Hydrogen Bond Acceptor Count | 22 |
| Rotatable Bond Count | 38 |
| Heavy Atom Count | 94 |
| Complexity | 2840 |
| Defined Atom Stereocenter Count | 10 |
| SMILES | S(C([H])([H])[H])C([H])([H])C([H])([H])[C@@]([H])(C(N([H])[C@]([H])(C(N([H])[C@]([H])(C(N([H])[H])=O)C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H])=O)C([H])([H])C(=O)O[H])=O)N([H])C([C@]([H])(C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12)N([H])C(C([H])([H])N([H])C([C@]([H])([C@@]([H])(C([H])([H])[H])O[H])N([H])C([C@]([H])(C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])OS(=O)(=O)O[H])N([H])C([C@]([H])(C([H])([H])C(=O)O[H])N([H])C([C@]([H])(C([H])([H])C([H])([H])C(N([H])[H])=O)N([H])C([C@]1([H])C([H])([H])C([H])([H])C(N1[H])=O)=O)=O)=O)=O)=O)=O)=O |
| InChi Key | YRALAIOMGQZKOW-HYAOXDFASA-N |
| InChi Code | InChI=1S/C58H73N13O21S2/c1-29(72)49(71-57(87)40(23-31-12-14-33(15-13-31)92-94(89,90)91)68-56(86)43(26-48(78)79)69-52(82)37(16-18-44(59)73)65-51(81)36-17-19-45(74)63-36)58(88)62-28-46(75)64-41(24-32-27-61-35-11-7-6-10-34(32)35)54(84)66-38(20-21-93-2)53(83)70-42(25-47(76)77)55(85)67-39(50(60)80)22-30-8-4-3-5-9-30/h3-15,27,29,36-43,49,61,72H,16-26,28H2,1-2H3,(H2,59,73)(H2,60,80)(H,62,88)(H,63,74)(H,64,75)(H,65,81)(H,66,84)(H,67,85)(H,68,86)(H,69,82)(H,70,83)(H,71,87)(H,76,77)(H,78,79)(H,89,90,91)/t29-,36+,37+,38+,39+,40+,41+,42+,43+,49+/m1/s1 |
| Chemical Name | (3S)-3-[[(2S)-5-amino-5-oxo-2-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]pentanoyl]amino]-4-[[(2S)-1-[[(2S,3R)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-(4-sulfooxyphenyl)propan-2-yl]amino]-4-oxobutanoic acid |
| Synonyms | Caerulein; Cerulein; FI-6934; FI 6934; Caerulein; Ceruletide; 17650-98-5; Cerulein; Ceruletida; Ceruletidum; 5-Oxo-L-prolyl-L-glutaminyl-L-alpha-aspartyl-O-sulfo-L-tyrosyl-L-threonylglycyl-L-tryptophyl-L-methionyl-L-alpha-aspartyl-L-phenylalaninamide; 5-Oxo-L-prolyl-L-glutaminyl-L-aspartyl-L-tyrosyl-L-threonylglycyl-L-tryptophyl-L-methionyl-L-aspartylphenyl-L-alaninamide 4-(hydrogen sulfate) (ester); FI6934 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | CCK receptor |
| ln Vitro | CeruLetide chemically and biologically interacts with the human gastrointestinal tract cholecystokinin-cholecystin (CCK) and gastrin II profiles. CeruLetide stimulates gallbladder contractions, extrapancreatic, gastric fluid and motility in the ICU duodenum, jejunum, ileum and sleep, while delaying gastric emptying and inhibiting motility in the proximal duodenum [1]. CeruLetide activates NF-kappaB/Rel in vitro at minimal physiological doses. This activation may induce a genetic program of self-defense before cellular damage occurs, which may terminate the higher degree of damage to pancreatic alveolar cells that occurs after chronic stress overstress [2]. |
| ln Vivo | Ceruletide can be used in animal modeling to construct animal pancreatitis models. CeruLetide (0.4-0.5 μg/kg, intravenous; 3-4 μg/kg, subcutaneous) causes vomiting and defecation in conscious intact dogs 15-30 minutes after intravenous injection and 2-4 hours after full recovery after sc administration. CeruLetide (5-15 ng/kg, iv) exhibits significant spasmogenic effects on the fecal pylorus. CeruLetide also reduces blood sugar in anesthetized dogs [1]. CeruLetide serum bile acid (SBA) stimulation circumvents the exogenous and endogenous effects associated with postprandial (PP) SBA stimulation. CeruLetide SBA stimulation may be as effective as PP SBA stimulation in dogs with cardiac portosystemic shunts (PSS) and may be more sensitive to liver dysfunction in dogs with confirmed respiratory disease (URD) [3]. |
| Enzyme Assay | Nuclear appearance of NF-kappaB/Rel-binding activity was detectable 15 minutes after cerulein injection. The DNA-binding activity consisted of NF-kappaB1 p50, NF-kappaB2 p52, and RelA p65 as judged by supershift assays and Western blot analysis. The onset and termination of NF-kappaB/Rel activation correlated with the degradation and reappearance of IkappaBalpha. Cerulein in supramaximal but not in physiological doses activated NF-kappaB/Rel in vitro. After blocking of NF-kappaB/Rel activation with pyrrolidine dithiocarbamate, the degree of morphological alterations was more pronounced than in controls, serum amylase and lactate dehydrogenase levels were significantly increased, and messenger RNA levels of pancreatitis-associated protein were more strongly induced, reflecting a more severe degree of pancreatitis. Similar results were obtained when N-acetyl-L-cysteine was used as an inhibitor of NF-kappaB activation. Conclusions: These data show that NF-kappaB/Rel is rapidly activated during cerulein pancreatitis. This activation may induce a self-defending genetic program before the onset of cellular injury, which might prevent higher degrees of damage of pancreatic acinar cells after secretagogue hyperstimulation.[3] |
| Animal Protocol |
Dogs: Serum bile acid (SBA) stimulation is administered to all dogs using food (<5 kg/body weight [BW] 2 teaspoons, >5 kg BW 2 tablespoons) or Ceruletide IM (0.3 μg/kg BW) on consecutive days. To reduce metabolic complications such as hepatic encephalopathy, a diet high in fiber and moderate in protein is recommended. The dogs fast for twelve hours prior to each test. At baseline, 60 and 120 minutes after feeding, and 20, 30, and 40 minutes after injection, blood samples are taken, in that order. The serum is used to measure SBA by a colorimetric test with endpoint determination after the blood samples are collected in plain tubes and allowed to clot. The samples are then centrifuged at 6,500 ×g for one minute[3]. Animals with portosystemic shunt (PSS) (n = 11) and dogs with upper respiratory disease (URD) (n = 9) were investigated. Healthy dogs (n = 13) and dogs with other diseases (n = 17) served as controls. Methods: All dogs underwent SBA stimulation with food and ceruletide. Stimulation blood samples were drawn at 60/120 minutes and 20/30/40 minutes, respectively. Results were compared statistically, and the sensitivity and specificity were determined with receiver-operating characteristic curves.[2] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Absorbed following intravenous administration. |
| References |
[1]. Pharmacology, clinical uses, and adverse effects of ceruletide, a cholecystokinetic agent. Pharmacotherapy. 1982 Jul-Aug;2(4):223-34. [2]. Comparison of postprandial and ceruletide serum bile acid stimulation in dogs. J Vet Intern Med . 2008 Jul-Aug;22(4):873-8. [3]. NF-kappaB/Rel activation in cerulein pancreatitis. Gastroenterology. 1999 Feb;116(2):420-30. [4]. Effects of cholecystokinin receptor agonist and antagonists on morphin dependence in mice. Pharmacol Toxicol. 1995 Dec;77(6):360-4. |
| Additional Infomation |
Pharmacodynamics Caerulein is a specific decapeptide similar in action and composition to the natural gastrointestinal peptide hormone cholecystokinin that stimulates gastric, biliary, and pancreatic secretion. It also exerts stimulatory actions on certain smooth muscles. |
Solubility Data
| Solubility (In Vitro) | DMSO: ~100 mg/mL (~73.9 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (1.23 mM) (saturation unknown) in 10% DMF 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.67 mg/mL (1.23 mM) (saturation unknown) in 10% DMF 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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. Solubility in Formulation 3: 1.67 mg/mL (1.23 mM) in 10% DMF 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Solubility in Formulation 4: 5%DMSO + 40%PEG300 + 5%Tween 80 + 50%ddH2O: 2.5mg/ml (1.85mM) Solubility in Formulation 5: 30.3 mg/mL (22.40 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. Solubility in Formulation 6: 2 mg/mL (1.48 mM) in Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; Need ultrasonic and adjust pH to 12 with 1M NaOH. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.7394 mL | 3.6971 mL | 7.3942 mL | |
| 5 mM | 0.1479 mL | 0.7394 mL | 1.4788 mL | |
| 10 mM | 0.0739 mL | 0.3697 mL | 0.7394 mL |