1027038-73-8Relevant articles and documents
Acyclic analogues of deoxyadenosine 3',5'-bisphosphates as P2Y1 receptor antagonists
Kim, Yong-Chul,Gallo-Rodriguez, Carola,Jang, Soo-Yeon,Nandanan, Erathodiyil,Adams, Mary,Harden, T. Kendall,Boyer, José L.,Jacobson, Kenneth A.
, p. 746 - 755 (2007/10/03)
P2Y1 receptors are activated by ADP and occur on endothelial cells, smooth muscle, epithelial cells, lungs, pancreas, platelets, and in the central nervous system. With the aid of molecular modeling, we have designed nucleotide analogues that act as selective antagonists at this subtype. The present study has tested the hypothesis that acyclic modifications of the ribose ring, proven highly successful for nucleoside antiviral agents such as gancyclovir, are generalizable to P2Y receptor ligands. Specifically, the binding site of the P2Y1 receptor was found to be sufficiently accommodating to allow the substitution of the ribose group with acyclic aliphatic and aromatic chains attached to the 9-position of adenine. Three groups of adenine derivatives having diverse side-chain structures, each containing two symmetrical phosphate or phosphonate groups, were prepared. Biological activity was demonstrated by the ability of the acyclic derivatives to act as agonists or antagonists in the stimulation of phospholipase C in turkey erythrocyte membranes. An acyclic N6-methyladenine derivative, 2-[2-(6- methylaminopurin-9-yl)-ethyl]-propane-1,3-bisoxy(diammoniumphosphate) (10), containing an isopentyl bisphosphate moiety, was a full antagonist at the P2Y1 receptor with an IC50 value of 1.60 μM. The corresponding 2-Cl derivative (11) was even more potent with an IC50 value of 0.84 μM. Homologation of the ethylene group at the 9-position to 3-5 methylene units or inclusion of cis- or trans-olefinic groups greatly reduced antagonist potency at the P2Y1 receptor. Analogues containing a diethanolamine amide group and an aryl di(methylphosphonate) were both less potent than 10 as antagonists, with IC50 values of 14 and 16 μM, respectively, and no agonist activity was observed for these analogues. Thus, the ribose moiety is clearly not essential for recognition by the turkey P2Y1 receptor, although a cyclic structure appears to be important for receptor activation, and the acyclic approach to the design of P2 receptor antagonists is valid.
