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首页> 外文期刊>Bioorganic and medicinal chemistry >Nucleotide analogues containing 2-oxa-bicyclo(2.2.1)heptane and l-alpha-threofuranosyl ring systems: interactions with P2Y receptors.
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Nucleotide analogues containing 2-oxa-bicyclo(2.2.1)heptane and l-alpha-threofuranosyl ring systems: interactions with P2Y receptors.

机译：包含2-氧杂双环（2.2.1）庚烷和l-α-呋喃呋喃糖基环系统的核苷酸类似物：与P2Y受体的相互作用。

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摘要

The ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of the P2Y(1) receptor has been successfully substituted with a rigid methanocarba ring system, leading to the conclusion that the North (N) ring conformation is preferred in receptor binding. Similarly, at P2Y(2) and P2Y(4) receptors, nucleotides constrained in the (N) conformation interact equipotently with the corresponding ribosides. We now have synthesized and examined as P2Y receptor ligands nucleotide analogues substituted with two novel ring systems: (1) a (N) locked-carbocyclic (cLNA) derivative containing the oxabicyclo[2.2.1]heptane ring system and (2) l-alpha-threofuranosyl derivatives. We have also compared potencies and preferred conformations of these nucleotides with the known anhydrohexitol-containing P2Y(1) receptor antagonist MRS2283. A cLNA bisphosphate derivative MRS2584 21 displayed a K(i) value of 22.5nM in binding to the human P2Y(1) receptor, and antagonized the stimulation of PLC by the potent P2Y(1) receptor agonist 2-methylthio-ADP (30nM) with an IC(50) of 650nM. The parent cLNA nucleoside bound only weakly to an adenosine receptor (A(3)). Thus, this ring system afforded some P2Y receptor selectivity. A l-alpha-threofuranosyl bisphosphate derivative 9 displayed an IC(50) of 15.3渭M for inhibition of 2-methylthio-ADP-stimulated PLC activity. l-alpha-Threofuranosyl-UTP 13 was a P2Y receptor agonist with a preference for P2Y(2) (EC(50)=9.9渭M) versus P2Y(4) receptors. The P2Y(1) receptor binding modes, including rotational angles, were estimated using molecular modeling and receptor docking.
机译：P2Y（1）受体的腺嘌呤核苷酸3'，5'-双磷酸拮抗剂的核糖部分已成功地被刚性的甲烷甲碳环系统取代，从而得出结论，在受体结合中优选North（N）环构象。类似地，在P2Y（2）和P2Y（4）受体上，受约束于（N）构象的核苷酸与相应的核苷等位相互作用。我们现在已经合成并检查了被两个新型环系统取代的P2Y受体配体核苷酸类似物：（1）包含氧杂双环[2.2.1]庚烷环系统的（N）锁碳环（cLNA）衍生物和（2）l- α-苏呋喃糖基衍生物。我们还与已知的含脱水己糖醇的P2Y（1）受体拮抗剂MRS2283比较了这些核苷酸的效力和优选构象。 cLNA双磷酸酯衍生物MRS2584 21在与人P2Y（1）受体结合时显示22.5nM的K（i）值，并与强大的P2Y（1）受体激动剂2-甲硫基ADP（30nM）拮抗PLC的刺激作用IC（50）为650nM。亲本cLNA核苷仅弱绑定到腺苷受体（A（3））。因此，该环系统提供了一些P2Y受体选择性。 1-α-硫代呋喃糖基二磷酸酯衍生物9显示出15.3μM的IC（50）用于抑制2-甲硫基-ADP刺激的PLC活性。 1-α-苏拉呋喃糖基-UTP 13是一种P2Y受体激动剂，相对于P2Y（4）受体，其优先选择P2Y（2）（EC（50）=9.9μM）。 P2Y（1）受体结合模式，包括旋转角度，是使用分子模型和受体对接估算的。

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