Extended N(6) substitution of rigid C2-arylethynyl nucleosides for exploring the role of extracellular loops in ligand recognition at the A3 adenosine receptor.
Extended N(6) substitution of rigid C2-arylethynyl nucleosides for exploring the role of extracellular loops in ligand recognition at the A3 adenosine receptor.
复制标题
刚性 C2-芳基乙炔基核苷的扩展 N(6) 取代，用于探索细胞外环在 A3 腺苷受体配体识别中的作用。
DOI：
10.1016/j.bmcl.2014.06.006
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发表时间：
2014
影响因子：
2.7
通讯作者：
Jacobson,KennethA
中科院分区：
文献类型：
--
作者：
Tosh,DilipK;Paoletta,Silvia;Chen,Zhoumou;Moss,StevenM;Gao,Zhan-Guo;Salvemini,Daniela;Jacobson,KennethA
合成了含N6-（反式-2-苯基环丙基）和2-苯基乙炔基的2-芳基乙炔基-（N）-甲烷氨基腺苷5′-甲基脲酰胺类激动剂，用于研究腺苷A3受体（AR）的结构特征。放射性配体结合证实了一个非对映体对的A3 AR选择性和N6 - 1 S，2 R立体选择性。受体结合，conformationally constrainedN 6组的环境进行了探讨，通过对接到A3 AR同源性模型，表明特定的疏水相互作用与第二个细胞外环能够调节的亲和力。2-在小鼠中口服吡啶基乙炔基衍生物18以减轻慢性压迫性损伤模型中的慢性神经性疼痛。
2-Arylethynyl-(N)-methanocarba adenosine 5′-methyluronamides containing rigidN6-(trans-2-phenylcyclopropyl) and 2-phenylethynyl groups were synthesized as agonists for probing structural features of the A3adenosine receptor (AR). Radioligand binding confirmed A3AR selectivity andN6-1S,2Rstereoselectivity for one diastereomeric pair. The environment of receptor-bound, conformationally constrainedN6groups was explored by docking to an A3AR homology model, indicating specific hydrophobic interactions with the second extracellular loop able to modulate the affinity profile. 2-Pyridylethynyl derivative18was administered orally in mice to reduce chronic neuropathic pain in the chronic constriction injury model.