Design and Synthesis of 2,6-Disubstituted-4'-Selenoadenosine-5'-<em>N</em>,<em>N</em>-Dimethyluronamide Derivatives as Human A₃ Adenosine Receptor Antagonists

• Main Authors: Hongseok Choi (Author), Kenneth A. Jacobson (Author), Jinha Yu (Author), Lak Shin Jeong (Author)
• Format: Book
• Published: MDPI AG, 2021-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph14040363; 1424-8247
• Keywords: A₃ adenosine receptor; structure-activity relationship; 4'-Selenonucleosides; antagonist; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 14, Iss 4, p 363 (2021)

A new series of 4'-selenoadenosine-5'-<i>N,N</i>-dimethyluronamide derivatives as highly potent and selective human A₃ adenosine receptor (hA₃AR) antagonists, is described. The highly selective A₃AR agonists, 4'-selenoadenosine-5'-<i>N</i>-methyluronamides were successfully converted into selective antagonists by adding a second <i>N</i>-methyl group to the 5'-uronamide position. All the synthesized compounds showed medium to high binding affinity at the hA₃AR. Among the synthesized compounds, 2-H-<i>N</i>⁶-3-iodobenzylamine derivative <b>9f</b> exhibited the highest binding affinity at hA₃AR. (<i>K_i</i> = 22.7 nM). The 2-H analogues generally showed better binding affinity than the 2-Cl analogues. The cAMP functional assay with 2-Cl-<i>N</i>⁶-3-iodobenzylamine derivative <b>9l</b> demonstrated hA₃AR antagonist activity. A molecular modelling study suggests an important role of the hydrogen of 5'-uronamide as an essential hydrogen bonding donor for hA₃AR activation.