Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A3 Adenosine Receptor Agonists.
Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A3 Adenosine Receptor Agonists.
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DOI：
10.1021/acs.jmedchem.5b01998
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发表时间：
2016-04-14
影响因子：
7.3
通讯作者：
Jacobson KA
中科院分区：
文献类型：
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作者：
Tosh DK;Ciancetta A;Warnick E;O'Connor R;Chen Z;Gizewski E;Crane S;Gao ZG;Auchampach JA;Salvemini D;Jacobson KA
嘌呤（N）-甲烷碳环-5′-N -烷基脲酰胺核糖苷A3腺苷受体（A3AR）激动剂在Sonogashira偶联及随后的氨解过程中发生了意外反应，从而产生了无环外胺的化合物。由于最初的C6 -甲基和C6 -苯乙烯基衍生物对A3AR具有出乎意料的高亲和力，因此制备了其他无环外胺的刚性核苷类似物。其中，C6 -甲基 -（2 -苯乙炔基）和C2 -（5 -氯噻吩乙炔基）类似物活性特别强，对人A3AR的Ki值分别为6和42 nM。此外，C2 -（5 -氯噻吩基）-6 - H类似物对A3AR具有强效和选择性（MRS7220，Ki为60 nM），并且还能完全逆转小鼠坐骨神经机械性异常性疼痛（体内，3 μmol/kg，口服）。通过同源建模以及这些高度修饰的核苷的对接，可以解释在无C6氢键供体的情况下仍能保持A3AR亲和力和效力的原因。该模型表明，稳定特征的适当组合可以部分弥补环外胺的缺失，而环外胺在A3AR结合位点的识别中通常是一个重要因素。
Purine (N)-methanocarba-5′-N-alkyluronamidoriboside A3 adenosine receptor (A3AR) agonists lacking an exocyclic amine resulted from an unexpected reaction during a Sonogashira coupling and subsequent aminolysis. Because the initial C6-Me and C6-styryl derivatives had unexpectedly high A3AR affinity, other rigid nucleoside analogues lacking an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl) and C2-(5-chlorothienylethynyl) analogues were particularly potent, with human A3AR Ki values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A3AR (MRS7220, Ki 60 nM) and also completely reversed mouse sciatic nerve mechanoallodynia (in vivo, 3 μmol/kg, po). The lack of a C6 H-bond donor while maintaining A3AR affinity and efficacy could be rationalized by homology modeling and docking of these hypermodified nucleosides. The modeling suggests that a suitable combination of stabilizing features can partially compensate for the lack of an exocyclic amine, an otherwise important contributor to recognition in the A3AR binding site.