Structure鈥揂ctivity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A2A and A3 Adenosine Receptor Ligands

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• 作者：Xiyan Hou ; Mahesh S. Majik ; Kyunglim Kim ; Yuna Pyee ; Yoonji Lee ; Varughese Alexander ; Hwa-Jin Chung ; Hyuk Woo Lee ; Girish Chandra ; Jin Hee Lee ; Seul-gi Park ; Won Jun Choi ; Hea Ok Kim ; Khai Phan ; Zhan-Guo Gao ; Kenneth A. Jacobson ; Sun Choi ; Sang Kook Lee ; Lak Shin Jeong
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January 12, 2012
• 年：2012
• 卷：55
• 期：1
• 页码：342-356
• 全文大小：619K
• 年卷期：v.55,no.1(January 12, 2012)
• ISSN：1520-4804

文摘

Truncated N⁶-substituted-4鈥?oxo- and 4鈥?thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A_2A and A₃ adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross-coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA_2AAR, but hydrophobic C8 substitution abolished binding at the hA_2AAR. However, most of synthesized compounds displayed medium to high binding affinity at the hA₃AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA_2AAR agonists. C2 substitution probed geometrically through hA_2AAR docking was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA_2AAR agonist and hA₃AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases.