In Vivo Phenotypic Screening for Treating Chronic Neuropathic Pain: Modification of C2-Arylethynyl Group of Conformationally Constrained A3 Adenosine Receptor Agonists

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• 作者：Dilip K. Tosh ; Amanda Finley ; Silvia Paoletta ; Steven M. Moss ; Zhan-Guo Gao ; Elizabeth T. Gizewski ; John A. Auchampach ; Daniela Salvemini ; Kenneth A. Jacobson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：December 11, 2014
• 年：2014
• 卷：57
• 期：23
• 页码：9901-9914
• 全文大小：712K
• ISSN：1520-4804

文摘

(N)-Methanocarba adenosine 5鈥?methyluronamides containing 2-arylethynyl groups were synthesized as A₃ adenosine receptor (AR) agonists and screened in vivo (po) for reduction of neuropathic pain. A small N⁶-methyl group maintained binding affinity, with human > mouse A₃AR and MW < 500 and other favorable physicochemical properties. E_max (maximal efficacy in a mouse chronic constriction injury pain model) of previously characterized A₃AR agonist, 2-(3,4-difluorophenylethynyl)-N⁶-(3-chlorobenzyl) derivative 6a, MRS5698, was surpassed. More efficacious analogues (in vivo) contained the following C2-arylethynyl groups: pyrazin-2-yl 23 (binding K_i, hA₃AR, nM 1.8), fur-2-yl 27 (0.6), thien-2-yl 32 (0.6) and its 5-chloro 33, MRS5980 (0.7) and 5-bromo 34 (0.4) equivalents, and physiologically unstable ferrocene 36, MRS5979 (2.7). 33 and 36 displayed particularly long in vivo duration (>3 h). Selected analogues were docked to an A₃AR homology model to explore the environment of receptor-bound C2 and N⁶ groups. Various analogues bound with 渭M affinity at off-target biogenic amine (M₂, 5HT_2A, 尾₃, 5HT_2B, 5HT_2C, and 伪_2C) or other receptors. Thus, we have expanded the structural range of orally active A₃AR agonists for chronic pain treatment.