Acyclic analogues of deoxyadenosine 3 ',5 '-bisphosphates as P2Y(1) receptor antagonists

P2Y(1) receptors are activated by ADP and occur on endothelial cells, smoot h muscle, epithelial cells, lungs, pancreas, platelets, and in the central nervous system. With the aid of molecular modeling, we have designed nucleo tide analogues that act as selective antagonists at this subtype. The prese nt study has tested the hypothesis that acyclic modifications of the ribose ring, proven highly successful for nucleoside antiviral agents such as gan cyclovir, are generalizable to P2Y receptor ligands. Specifically, the bind ing site of the P2Y(1) receptor was found to be sufficiently accommodating to allow the substitution of the ribose group with acyclic aliphatic and ar omatic chains attached to the 9-position of adenine. Three groups of adenin e derivatives having diverse side-chain structures, each containing two sym metrical phosphate or phosphonate groups, were prepared. Biological. activi ty was demonstrated by the ability of the acyclic derivatives to act as ago nists or antagonists in the stimulation of phospholipase C in turkey erythr ocyte membranes. An acyclic N-6-methyladenine derivative, 2-[2(6-methylamin opurin-9-yl)-ethyl]-propane-1,3-bisoxy(diammoniumphosphate) (10), containin g an isopentyl bisphosphate moiety, was a full antagonist at the P2Y(1) rec eptor with an IC50 value of 1.60 mu M. The corresponding 2-Cl derivative (1 1) was even more potent with an IC50 value of 0.84 mu M Homologation of the ethylene group at the g-position to 3-5 methylene units or inclusion of ci s- or trans-olefinic groups greatly reduced antagonist potency at the P2Y(1 ) receptor. Analogues containing a diethanolamine amide group and an aryl d i(methylphosphonate) were both less potent than 10 as antagonists, with IC5 0 values of 14 and 16 mu M, respectively, and no agonist activity was obser ved for these analogues. Thus, the ribose moiety is clearly not essential f or recognition by the turkey P2Y(1) receptor, although a cyclic structure a ppears to be important for receptor activation, and the acyclic approach to the design of P2 receptor antagonists is valid.