Preladenant

SKU: orb1302982

Description

Preladenant (SCH-420814) is a potent and highly selective adenosine A2A receptor antagonist with a Ki of 1.1 nM and over 1000-fold selectivity versus other adenosine subtypes. This orally bioavailable small molecule is a valuable research tool for investigating Parkinson's disease, both in vitro and in animal models.

Research Area

Immunology & Inflammation, Neuroscience

Key Properties

• CAS Number: 377727-87-2
• MW: 503.57
• Purity: >98%
• Formula: C₂₅H₂₉N₉O₃
• SMILES: COCCOc1ccc(cc1)N1CCN(CCn2ncc3c2nc(N)n2nc(nc32)-c2ccco2)CC1
• Target: GPCR
• Solubility: Soluble in DMSO ( 5 mg/ml with warming)

Bioactivity

• Target IC50:
  A2A receptor:Ki: 1.1 nM
• In Vivo:
  Preladenant (1 mg/kg) inhibits L-Dopa-induced behavioral sensitization and exhibits antidepressant-like profiles in the mouse tail suspension and mouse and rat forced swim tests. It dose-dependently reduces parkinsonian scores, achieving minimum scores of 9.0 at 1 mg/kg and 6.5 at 3 mg/kg. A subthreshold dose of Preladenant lowers minimum and mean parkinsonian scores in animals treated with 3 mg/kg of L-Dopa to 5.25 and 6.88, respectively. A Wilcoxin test shows significant improvements in minimum parkinsonian scores with Preladenant (3 mg/kg), L-Dopa (3, 6, and 12 mg/kg), and Preladenant plus L-Dopa (1 or 3 mg/kg + 3 mg/kg). Additionally, both the 12 mg/kg L-Dopa and L-Dopa + Preladenant groups significantly improve minimal and mean parkinsonian scores, comparable to the 3 mg/kg L-Dopa group.
• In Vitro:
  In cells expressing the recombinant human A2A receptor, Preladenant completely antagonizes cAMP. The KB values of Preladenant is 1.3 nM at the A2A receptor. A similar functional assay with A2B receptor-expressing cells is used to demonstrate selectivity over A2B receptors. In this assay, the KB value for Preladenant is 1.2 μM and this selectivity for the A2A receptor is 923-fold over the A2B receptor.
• Cell Research:
  Preladenant is dissolved in DMSO and stored, and then diluted with appropriate media before use.HEK 293 cells stably expressing either human A2A or A2B receptors are grown to confluence, harvested using enzyme-free cell dissociation buffer and pelleted by centrifugation (1000 g; 5 min). The cells are washed and diluted to a final density of 4×106 cells/mL in Hanks' balanced salt solution supplemented with 10 nM HPS, pH 7.4, 5 mM MgCl2, and 0.2% bovine serum albumin. Preladenant is diluted in the above buffer with the inclusion of the following components to achieve the respective final assay concentrations: 0.25% DMSO, 2 U/mL adenosine deaminase, and 100 μM Ro 201724. Cell suspensions (20 μL) are preincubated for 15 min at room temperature in 96-well plates containing 25 μL of vehicle or Preladenant. CGS-21680 (A2A) or 5-N-cyclopropylcarboxamidoadenosine (A2B) at 10-fold the desired concentration is then added, and the reactions are incubated for 15 min at 37°C. The reactions are terminated by the addition of 50 μL of assay/lysis buffer.
• Animal Research:
  Preladenant is prepared in 50% polyethylene glycol 400 (Rats and Mice).Preladenant is dissolved in cyclodextrin, sonicated and administered p.o. for the study (Monkey).Male CD rats and male CD1 mice are used. Preladenant is administered orally in 50% polyethylene glycol 400 at a dose volume of 3 to 5 mL/kg. In the forced swim test (FST), mice are placed individually into glass cylinders filled to a depth of 10 cm with water (25°C) and left for 6 min. A mouse is judged to be immobile when it floats in an upright position and made only small movements to keep its head above water. The duration of immobility is recorded during the last 4 min of the 6-min testing period by an observer blind to the treatment of the animals. Animals are dosed with vehicle, Preladenant, or SCH 412348 1 h before behavioral testing. Each rat is placed individually in a cylinder of water (25°C) and left to swim for 15 min before being removed and dried in a heated enclosure and returned its home cage. Twenty-four hours later (test day), the animal is re-exposed to the conditions, and the total immobility time during a 5-min period is recorded. In addition, the duration of time that the rats spent climbing the sides of the cylinder is recorded. On test day, each animal is dosed with Preladenant, SCH 412348, or vehicle 1 h before behavioral testing. Six female cynomolgus (Macaca fascicularis) monkeys (weighing 3.5-4.2 kg) are used. The animals are rendered parkinsonian by subcutaneous (sc) administrations of MPTP (2-3 mg/kg) once per week until a stable parkinsonian syndrome (unchanged disability score of 8 or greater for at least a month) developed as measured by a parkinsonian disability scale. At least 2 months after the final administration of MPTP, the monkeys are treated chronically with Prolopa (L-Dopa/benserazide, 100/25 mg) until clear and reproducible dyskinesias developed. The present experiment with L-Dopa and Preladenant (1 mg/kg and 3 mg/kg, p.o.) is performed in these monkeys.

Storage & Handling

• Storage: -20°C
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

SCH 420814

Compound Identifiers

PubChem CID

10117987