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| Targets |
The primary targets are the Calcitonin gene-related peptide receptors, which are heterodimers consisting of the Calcitonin receptor-like receptor (CLR) and the Receptor activity-modifying protein 1 (RAMP1). The free acid form of CGRP is thought to have altered binding affinity and bioactivity compared to the amidated form, making it a tool for studying the importance of C-terminal amidation.
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| ln Vitro |
In vitro, the free acid form of CGRP is used as a control to study the structure-activity relationship (SAR) of the CGRP peptide. Compared to the amidated, biologically active form, the free acid exhibits significantly reduced receptor binding affinity and biological activity. It is therefore a critical negative control in assays measuring CGRP-mediated effects, helping to confirm that observed responses are due to the active amidated peptide and not non-specific effects or contaminants.
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| ln Vivo |
CGRP is a well-known potent vasodilator and plays a significant role in migraine pathophysiology. The free acid form of CGRP has been studied for its role in nociception (pain perception), ingestive behavior, and modulation of the endocrine system. It is used in animal models to differentiate between the actions of the amidated and non-amidated forms. It is released in response to inflammation and bacterial infections, and it is a key mediator in neurogenic inflammation.
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| Enzyme Assay |
A standard in vitro cell-free binding assay for CGRP receptor uses membranes prepared from cells that express the CLR/RAMP1 receptor complex. The membranes are incubated with a radiolabeled ligand, such as 125I-labeled amidated CGRP, and varying concentrations of unlabeled test peptides (amidated CGRP, free acid CGRP, antagonists). Bound radioligand is separated from free by filtration, and the radioactivity is counted. The inhibition constant (Ki) for the free acid CGRP is typically higher (lower affinity) than that of the amidated form.
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| Cell Assay |
CGRP receptor activation is typically studied in cells that endogenously express the receptor or are transfected with CLR and RAMP1. The functional readout is often the accumulation of intracellular cAMP, as the receptor is Gs-coupled. Cells are treated with forskolin and the test peptide (amidated CGRP, free acid CGRP, or antagonists) in the presence of a phosphodiesterase inhibitor. The amount of cAMP produced is then quantified using a competitive immunoassay (ELISA). This allows for the calculation of EC50 values for agonism, showing reduced potency for the free acid form.
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| Animal Protocol |
The in vivo activity of CGRP and its analogs is typically studied in rodent models of pain and migraine. For example, a model of acute pain or migraine involves administering a stimulus (such as nitroglycerin or inflammatory soup) to the animal. The test compound (amidated or free acid CGRP) is then administered, often intravenously (IV) to study vasodilation, or directly into the brain. Endpoints include measuring changes in blood flow (e.g., in the meningeal artery) or behavioral signs of pain. The free acid form is used as a negative control.
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| ADME/Pharmacokinetics |
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Pharmacokinetic studies focus on the native, amidated peptide. For research purposes, peptides like CGRP free acid are typically dissolved in sterile water or a dilute acetic acid solution to ensure solubility. They are often administered via intravenous (IV) injection to study systemic effects or via microinjection into specific brain regions for CNS studies. They are susceptible to proteolytic degradation in serum, leading to a short half-life.
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| Toxicity/Toxicokinetics |
D-Toxicity data for the synthetic human CGRP free acid peptide is not extensively documented in standard literature. The native, amidated CGRP is an endogenous signaling molecule with a known safety profile when released naturally. In research settings, toxicity is dose-dependent. Administration of very high doses of CGRP can cause significant hypotension due to its potent vasodilatory effects. As with any peptide, potential immunogenicity and injection site reactions are considered, but specific toxicology data for the free acid form is not a standard focus.
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| References |
[1]. M G Rosenfeld, Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature. 1983 Jul;304(5922):129-35.
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| Additional Infomation |
Procalcitonin is being investigated in the clinical trial NCT03440060 (Procalcitonin-guided antibiotic treatment for acute exacerbations of chronic obstructive pulmonary disease). Procalcitonin is a precursor peptide hormone of calcitonin. It is normally present in low serum levels, but during inflammation and bacterial infection, it is released into the bloodstream primarily by neuroendocrine cells in the lungs and intestines. It is a diagnostic marker for bacteremia.
Calcitonin gene-related peptide (CGRP) is a neuropeptide widely distributed in the central and peripheral nervous system, where it functions as a potent vasodilator and a key mediator in pain transmission, particularly in migraine. The amidated form at the C-terminus is critical for its high-affinity receptor binding and biological activity. The free acid version is an important research tool for structure-activity relationship (SAR) studies to delineate the importance of this C-terminal amidation. This peptide is not a drug but a research tool, and it is not clinically approved. CGRP and its receptor (CLR/RAMP1) are, however, major targets for modern migraine therapies, including monoclonal antibodies (e.g., erenumab, galcanezumab) and small molecule gepants (e.g., ubrogepant). |
| Molecular Formula |
C163H266N50O50S2
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|---|---|
| Molecular Weight |
3790.2911734581
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| Exact Mass |
3788.928
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| CAS # |
83652-28-2
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| PubChem CID |
56841902
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
-16.3
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| Hydrogen Bond Donor Count |
57
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| Hydrogen Bond Acceptor Count |
58
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| Rotatable Bond Count |
112
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| Heavy Atom Count |
265
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| Complexity |
9010
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| Defined Atom Stereocenter Count |
37
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| SMILES |
C[C@H]1C(=O)N[C@H](C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N1)[C@@H](C)O)CC(=O)O)NC(=O)[C@H](C)N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC2=CN=CN2)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CO)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC3=CC=CC=C3)C(=O)N[C@@H](C(C)C)C(=O)N4CCC[C@H]4C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC5=CC=CC=C5)C(=O)O)[C@@H](C)O
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| InChi Key |
PBGNJGVTFINXOG-XJVRLEFXSA-N
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| InChi Code |
InChI=1S/C163H266N50O50S2/c1-73(2)52-96(185-116(225)65-178-130(231)82(18)182-138(239)97(53-74(3)4)191-136(237)94(44-35-49-175-162(170)171)187-141(242)100(57-91-62-174-72-181-91)197-158(259)128(88(24)220)212-155(256)123(79(13)14)206-150(251)110-71-265-264-70-109(202-129(230)81(17)166)149(250)196-104(61-119(228)229)146(247)210-125(85(21)217)156(257)184-84(20)132(233)209-126(86(22)218)159(260)203-110)139(240)192-98(54-75(5)6)140(241)201-108(69-216)148(249)189-95(45-36-50-176-163(172)173)137(238)200-106(67-214)133(234)179-63-115(224)177-64-118(227)204-121(77(9)10)154(255)207-122(78(11)12)153(254)190-93(43-32-34-48-165)135(236)194-101(58-112(167)221)143(244)195-102(59-113(168)222)142(243)193-99(55-89-38-27-25-28-39-89)144(245)208-124(80(15)16)160(261)213-51-37-46-111(213)151(252)211-127(87(23)219)157(258)198-103(60-114(169)223)145(246)205-120(76(7)8)152(253)180-66-117(226)186-107(68-215)147(248)188-92(42-31-33-47-164)134(235)183-83(19)131(232)199-105(161(262)263)56-90-40-29-26-30-41-90/h25-30,38-41,62,72-88,92-111,120-128,214-220H,31-37,42-61,63-71,164-166H2,1-24H3,(H2,167,221)(H2,168,222)(H2,169,223)(H,174,181)(H,177,224)(H,178,231)(H,179,234)(H,180,253)(H,182,239)(H,183,235)(H,184,257)(H,185,225)(H,186,226)(H,187,242)(H,188,248)(H,189,249)(H,190,254)(H,191,237)(H,192,240)(H,193,243)(H,194,236)(H,195,244)(H,196,250)(H,197,259)(H,198,258)(H,199,232)(H,200,238)(H,201,241)(H,202,230)(H,203,260)(H,204,227)(H,205,246)(H,206,251)(H,207,255)(H,208,245)(H,209,233)(H,210,247)(H,211,252)(H,212,256)(H,228,229)(H,262,263)(H4,170,171,175)(H4,172,173,176)/t81-,82-,83-,84-,85+,86+,87+,88+,92-,93-,94-,95-,96-,97-,98-,99-,100-,101-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,120-,121-,122-,123-,124-,125-,126-,127-,128-/m0/s1
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| Chemical Name |
(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S,3R)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-4-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(4R,7S,10S,13S,16S,19R)-19-[[(2S)-2-aminopropanoyl]amino]-16-(carboxymethyl)-7,13-bis[(1R)-1-hydroxyethyl]-10-methyl-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]amino]-3-methylbutanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]acetyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxypropanoyl]amino]acetyl]amino]acetyl]amino]-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]hexanoyl]amino]-4-oxobutanoyl]amino]-4-oxobutanoyl]amino]-3-phenylpropanoyl]amino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoyl]amino]-4-oxobutanoyl]amino]-3-methylbutanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]propanoyl]amino]-3-phenylpropanoic acid
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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) |
H2O: 25 mg/mL (6.60 mM)
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| Solubility (In Vivo) |
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.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] Oral Formulations
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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.2638 mL | 1.3192 mL | 2.6383 mL | |
| 5 mM | 0.0528 mL | 0.2638 mL | 0.5277 mL | |
| 10 mM | 0.0264 mL | 0.1319 mL | 0.2638 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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