Structure-Guided Design of A3 Adenosine Receptor-Selective Nucleosides: Combination of 2-Arylethynyl and Bicyclo[3.1.0]hexane Substitutions

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• 作者：Dilip K. Tosh ; Francesca Deflorian ; Khai Phan ; Zhan-Guo Gao ; Tina C. Wan ; Elizabeth Gizewski ; John A. Auchampach ; Kenneth A. Jacobson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 24, 2012
• 年：2012
• 卷：55
• 期：10
• 页码：4847-4860
• 全文大小：514K
• 年卷期：v.55,no.10(May 24, 2012)
• ISSN：1520-4804

文摘

(N)-Methanocarba adenosine 5鈥?methyluronamides containing known A₃ AR (adenosine receptor)-enhancing modifications, i.e., 2-(arylethynyl)adenine and N⁶-methyl or N⁶-(3-substituted-benzyl), were nanomolar full agonists of human (h) A₃AR and highly selective (K_i 0.6 nM, N⁶-methyl 2-(halophenylethynyl) analogues 13 and 14). Combined 2-arylethynyl-N⁶-3-chlorobenzyl substitutions preserved A₃AR affinity/selectivity in the (N)-methanocarba series (e.g., 3,4-difluoro full agonist MRS5698 31, K_i 3 nM, human and mouse A₃) better than that for ribosides. Polyaromatic 2-ethynyl N⁶-3-chlorobenzyl analogues, such as potent linearly extended 2-p-biphenylethynyl MRS5679 34 (K_i hA₃ 3.1 nM; A₁, A_2A, inactive) and fluorescent 1-pyrene adduct MRS5704 35 (K_i hA₃ 68.3 nM), were conformationally rigid; receptor docking identified a large, mainly hydrophobic binding region. The vicinity of receptor-bound C2 groups was probed by homology modeling based on recent X-ray structure of an agonist-bound A_2AAR, with a predicted helical rearrangement requiring an agonist-specific outward displacement of TM2 resembling opsin. Thus, the X-ray structure of related A_2AAR is useful in guiding the design of new A₃AR agonists.