Nucleotide analogues containing 2-oxa-bicyclo[2.2.1]heptane and l-b1;-threofuranosyl ring systems: interactions with P2Y receptors

详细信息    查看全文

• 作者：Ohno ; Michihiro ; Costanzi ; Stefano ; Kim ; Hak Sung ; Kempeneers ; Veerle ; Vastmans ; Karen ; Herdewijn ; Piet ; et. al.
• 关键词：Nucleoside ; Purine ; Pyrimidine ; G protein-coupled receptor ; Carbocyclic ; Phospholipase C ; Radioligand binding ; Molecular model
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2004
• 出版时间：November 1, 2004
• 年：2004
• 卷：12
• 期：21
• 页码：5619-5630
• 全文大小：554 K

文摘

The ribose moiety of adenine nucleotide 3aaa,5aaa-bisphosphate antagonists of the P2Yb>1b> 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 P2Yb>2b> and P2Yb>4b> 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-aa-threofuranosyl derivatives. We have also compared potencies and preferred conformations of these nucleotides with the known anhydrohexitol-containing P2Yb>1b> receptor antagonist MRS2283. A cLNA bisphosphate derivative MRS2584 <b>21b> displayed a Kb>ib> value of 22.5nM in binding to the human P2Yb>1b> receptor, and antagonized the stimulation of PLC by the potent P2Yb>1b> receptor agonist 2-methylthio-ADP (30nM) with an ICb>50b> of 650nM. The parent cLNA nucleoside bound only weakly to an adenosine receptor (Ab>3b>). Thus, this ring system afforded some P2Y receptor selectivity. A l-aa-threofuranosyl bisphosphate derivative <b>9b> displayed an ICb>50b> of 15.3aaM for inhibition of 2-methylthio-ADP-stimulated PLC activity. l-aa-Threofuranosyl-UTP <b>13b> was a P2Y receptor agonist with a preference for P2Yb>2b> (ECb>50