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Purity: ≥98%
Preladenant (formerly known as MK-3814; SCH-420814) is a novel potent, selective and competitive antagonist of adenosine A2A receptor with potential immunomodulatory effects and may be used for the treatment for Parkinson's disease. It has >1000-fold selectivity over all other adenosine receptors and inhibits the adenosine A2A receptor with a Ki of 0.6 nM. It was studied in a phase 2 trial to treat Parkinson's disease, but the results did not show the anticipated effectiveness. Following repeated daily administration, preladenant (1 mg/kg) inhibited L-Dopa-induced behavioral sensitization, suggesting a decreased risk of developing dyskinesias. Last but not least, in behavioral despair models such as the mouse tail suspension test and the mouse and rat forced swim test, preladenant and SCH 412348 showed antidepressant-like profiles.
| Targets |
Adenosine A2A receptor ( Ki = 1.1 nM )
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| ln Vitro |
Preladenant likewise totally opposes cAMP in cells that have the human A2A receptor recombinant expressed. At the A2A receptor, preladenant is found to have KB values of 1.3 nM; this value is in good agreement with the Ki value found in the radioligand binding assay. To show selectivity over A2B receptors, a functional test aKin to this one is performed using cells that express A2B receptors. Preladenant's KB value in this assay is 1.2 μM, meaning that it is 923 times more selective for the A2A receptor than the A2B receptor[1].
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| ln Vivo |
Preladenant (1 mg/kg) prevents behavioral sensitization caused by L-Dopa following daily administration, indicating a lower chance of dysKinesia development. Preladenant demonstrates antidepressant-like characteristics in behavioral despair models, such as the forced swim test for rats and mice and the tail suspension test for mice[1]. At doses of 1 mg/kg (minimum score: 9.0) and 3 mg/kg (minimum score: 6.5), preladenant reduces parKinsonian scores in a dose-dependent manner. Preladenant at a subthreshold dose lowers the mean and minimum parKinsonian scores in animals receiving 3 mg kg of L-Dopa to 6.88 and 5.25, respectively. To compare individual treatments to the vehicle, the Wilcoxin test is employed. The minimum parKinsonian score is markedly improved by Preladenant (3 mg/kg), L-Dopa (3, 6, and 12 mg/kg), and the combination of Preladenant and L-Dopa (1 or 3 mg/kg+3 mg/kg). Furthermore, in comparison to the 3 mg/kg L-Dopa group, the minimum and mean parKinsonian scores of the 12 mg/kg L-Dopa and L-Dopa+Preladenant groups show a significant improvement[2].
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| Enzyme Assay |
Receptor binding is performed using membranes prepared from cells with recombinant expression of adenosine receptors as follows: human A2A and HEK 293, rat A2A and Chinese hamster ovary, human and rat A1 and Chinese hamster ovary, and human A3 and HEK 293. To conduct radioligand competition binding assays, 200 μL of total assay volume are used in 96-well plates, with a final test drug concentration range of 0.1–3 μM. A1 and A2A, Dulbecco's phosphate-buffered saline with 10 mM MgCl2, and A3, 50 mM Tris-HCl, 120 mM NaCl, and 10 mM MgCl2 are the assay buffers (pH 7.4) in which membranes are diluted. The membrane preparations are incubated at room temperature for 15 minutes after 4 U/mL adenosine deaminase is added to them in order to eliminate endogenous adenosine from them. At 0.5 ([3H]SCH 58261, A2A), 1 ([3H]DPCPX, A1), or 0.25 ([125I]AB-MECA, A3) nM, radioligand is added. The addition of 100 nM NECA (A1), 100 nM CGS 15923 (A2A), or 100 nM DPCPX (A3) defines nonspecific binding. For 1.5 hours (A2A and A1) or 2 hours (A3), plates are incubated at room temperature with agitation. Using a Brandel cell harvester, membranes are filtered onto Packard GF-B filter plates and then cleaned in ice-cold assay buffer to separate the radioligand that is bound and free. Prior to filling each well with 45 μL of Microscint 20, the plates are dried. Using an iterative curve-fitting program, the displacement curves are fitted in order to determine the IC50 values. The Cheng-Prusoff equation[1] is used to calculate Ki values.
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| Cell Assay |
Human A2A or human A2B receptor-stably expressing HEK 293 cells are cultured to confluence, harvested with an enzyme-free cell dissociation buffer, and pelleted via centrifugation (1000 g; 5 min). The cells are rinsed and diluted in Hanks' balanced salt solution supplemented with 10 nM HPS, pH 7.4, 5 mM MgCl2, and 0.2% bovine serum albumin until they reach a final density of 4×106 cells/mL. To attain the desired final assay concentrations, the preladenant is diluted in the buffer mentioned above and mixed with the following ingredients: 100 μM Ro 201724, 2 U/mL adenosine deaminase, and 0.25% DMSO. In 96-well plates with 25 μL of vehicle or preladenant, cell suspensions (20 μL) are preincubated for 15 min at room temperature. After adding 10-fold the desired concentration of either 5-N-cyclopropylcarboxamidoadenosine (A2B) or CGS-21680 (A2A), the reactions are incubated for 15 minutes at 37°C. After adding 50 μL of assay/lysis buffer, the reactions come to an end. Plotting of the concentration response curves for CGS-21680 with and without preladenant allows for the determination of the EC50 values through curve fitting with GraphPad Prism software[1].
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| Animal Protocol |
Mice and Rats: Male CD1 mice and male CD rats are employed. Preladenant is taken orally at a dose volume of 3 to 5 milliliters per Kilogram in 50% polyethylene glycol 400. Mice are put one at a time into glass cylinders that are filled with water (25°C) to a depth of 10 cm in the forced swim test (FST), and they are left for six minutes. When a mouse floats upright and makes only tiny movements to keep its head above water, it is considered immobile. During the final four minutes of the six-minute testing period, an observer who is blind to the animals' treatments records the length of immobility. Preladenant, SCH 412348, or the vehicle is dosed into the animals one hour prior to behavioral testing. After swimming for fifteen minutes in a 25°C water cylinder, each rat is taken out, dried in a heated enclosure, and then placed back in its original cage. The animal is reexposed to the conditions on test day, which is twenty-four hours later. The duration of immobility during a five-minute period is then recorded. Furthermore, the amount of time the rats spent scaling the cylinder's walls is noted. One hour prior to behavioral testing on test day, each animal receives a dose of Preladenant, SCH 412348, or vehicle.
Monkeys: Six 3.5–4.2 kg female Macaca fascicularis cynomolgus monkeys are utilized. The animals are given subcutaneous (sc) injections of MPTP (2–3 mg/kg) once a week until they develop a stable parKinsonian syndrome, which is defined as an unchanged disability score of 8 or higher for at least one month, as determined by a parKinsonian disability scale. After the last MPTP administration, the monkeys receive chronic Prolopa treatment (L-Dopa/benserazide, 100/25 mg) for at least two months, or until the development of distinct and observable dysKinesias. Using L-Dopa and Preladenant (1 mg/kg and 3 mg/kg, p.o.) on these monkeys is the current experiment.
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| References |
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| Additional Infomation |
Preladenant has been used in trials studying the treatment of Brain Diseases, Parkinson Disease, Movement Disorders, Antipsychotic Agents, and Parkinsonian Disorders, among others.
Preladenant is an orally bioavailable antagonist of the adenosine A2A receptor (A2AR; ADORA2A), with potential immunomodulating and antineoplastic activities. Upon administration, preladenant selectively binds to and inhibits A2AR expressed on T-lymphocytes. This blocks tumor-released adenosine from interacting with A2AR and prevents the adenosine/A2AR-mediated inhibition of T-lymphocytes. This results in the proliferation and activation of T-lymphocytes, and stimulates a T-cell-mediated immune response against tumor cells. A2AR, a G protein-coupled receptor, is highly expressed on the cell surfaces of T-cells and, upon activation by adenosine, inhibits T-cell proliferation and activation. Adenosine is often overproduced by cancer cells and plays a key role in immunosuppression. |
| Molecular Formula |
C25H29N9O3
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| Molecular Weight |
503.57
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| Exact Mass |
503.239
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| Elemental Analysis |
C, 59.63; H, 5.80; N, 25.03; O, 9.53
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| CAS # |
377727-87-2
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| Related CAS # |
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| PubChem CID |
10117987
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| Appearance |
White to off-white solid powder
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| LogP |
2.747
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
37
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| Complexity |
722
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O(C([H])([H])C([H])([H])OC([H])([H])[H])C1C([H])=C([H])C(=C([H])C=1[H])N1C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])N2C3=C(C4=NC(C5=C([H])C([H])=C([H])O5)=NN4C(N([H])[H])=N3)C([H])=N2)C([H])([H])C1([H])[H]
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| InChi Key |
DTYWJKSSUANMHD-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H29N9O3/c1-35-15-16-36-19-6-4-18(5-7-19)32-11-8-31(9-12-32)10-13-33-23-20(17-27-33)24-28-22(21-3-2-14-37-21)30-34(24)25(26)29-23/h2-7,14,17H,8-13,15-16H2,1H3,(H2,26,29)
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| Chemical Name |
4-(furan-2-yl)-10-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-1-yl]ethyl]-3,5,6,8,10,11-hexazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-amine
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 0.5 mg/mL (0.99 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 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. Solubility in Formulation 2: 0.5 mg/mL (0.99 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 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. View More
Solubility in Formulation 3: ≥ 0.5 mg/mL (0.99 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 | 1.9858 mL | 9.9291 mL | 19.8582 mL | |
| 5 mM | 0.3972 mL | 1.9858 mL | 3.9716 mL | |
| 10 mM | 0.1986 mL | 0.9929 mL | 1.9858 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01465412 | Completed | Drug: Preladenant | Chronic Hepatic Impairment | Merck Sharp & Dohme LLC | November 10, 2011 | Phase 1 |
| NCT01323855 | Completed | Drug: Preladenant | Alcohol Withdrawal | Merck Sharp & Dohme LLC | March 28, 2011 | Phase 1 |
| NCT00845000 | Completed | Drug: Placebo Drug: Levodopa |
Parkinson Disease | Merck Sharp & Dohme LLC | April 21, 2009 | Phase 1 |
| NCT00406029 | Completed | Drug: Preladenant Drug: Placebo Drug: L-dopa |
Parkinson Disease Movement Disorders |
Merck Sharp & Dohme LLC | November 20, 2006 | Phase 2 |
| NCT01227265 | Completed | Drug: Preladenant Drug: Placebo |
Idiopathic Parkinson Disease Parkinson Disease |
Merck Sharp & Dohme LLC | November 19, 2010 | Phase 3 |
 ACS Chem Neurosci. 2011 Oct 19; 2(10): 555–567. |
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 ACS Chem Neurosci. 2011 Oct 19; 2(10): 555–567. |
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