264610-97-1Relevant articles and documents
Ring-constrained (N)-methanocarba nucleosides as adenosine receptor agonists: Independent 5′-uronamide and 2′-deoxy modifications
Lee, Kyeong,Ravi, Gnana,Ji, Xiao-Duo,Marquez, Victor E.,Jacobson, Kenneth A.
, p. 1333 - 1337 (2001)
Novel methanocarba adenosine analogues, having the pseudo-ribose northern (N) conformation preferred at adenosine receptors (ARs), were synthesized and tested in binding assays. The 5′-uronamide modification preserved [N6-(3-iodobenzyl)] or enhanced (N6-methyl) affinity at A3ARs, while the 2′-deoxy modification reduced affinity and efficacy in a functional assay.
Synthesis, biological activity, and molecular modeling of ribose- modified deoxyadenosine bisphosphate analogues as P2Y1 receptor ligands
Nandanan, Erathodiyil,Jang, Soo-Yeon,Moro, Stefano,Kim, Hea Ok,Siddiqui, Maqbool A.,Russ, Pamela,Marquez, Victor E.,Busson, Roger,Herdewijn, Piet,Harden, T. Kendall,Boyer, José L.,Jacobson, Kenneth A.
, p. 829 - 842 (2007/10/03)
The structure-activity relationships of adenosine-3',5'-bisphosphates as P2Y1 receptor antagonists have been explored, revealing the potency- enhancing effects of the N6-methyl group and the ability to substitute the ribose moiety (Nandanan et al. J. Med. Chem. 1999, 42, 1625-1638). We have introduced constrained carbocyclic rings (to explore the role of sugar puckering), non-glycosyl bonds to the adenine moiety, and a phosphate group shift. The biological activity of each analogue at P2Y1 receptors was characterized by measuring its capacity to stimulate phospholipase C in turkey erythrocyte membranes (agonist effect) and to inhibit its stimulation elicited by 30 nM 2-methylthioadenosine-5'-diphosphate (antagonist effect). Addition of the N6-methyl group in several cases converted pure agonists to antagonists. A carbocyclic N6-methyl-2'-deoxyadenosine bisphosphate analogue was a pure P2Y1 receptor antagonist and equipotent to the ribose analogue (MRS 2179). In the series of ring-constrained methanocarba derivatives where a fused cyclopropane moiety constrained the pseudosugar ring of the nucleoside to either a Northern (N) or Southern (S) conformation, as defined in the pseudorotational cycle, the 6-NH2 (N)-analogue was a pure agonist of EC50 155 nM and 86-fold more potent than the corresponding (S)-isomer. The 2-chloro-N6-methyl-(N)-methanocarba analogue was an antagonist of IC50 51.6 nM. Thus, the ribose ring (N)-conformation appeared to be favored in recognition at P2Y1 receptors. A cyclobutyl analogue was an antagonist with IC50 of 805 nM, while morpholine ring-containing analogues were nearly inactive. Anhydrohexitol ring-modified bisphosphate derivatives displayed micromolar potency as agonists (6-NH2) or antagonists (N6-methyl). A molecular model of the energy-minimized structures of the potent antagonists suggested that the two phosphate groups may occupy common regions. The (N)- and (S)-methanocarba agonist analogues were docked into the putative binding site of the previously reported P2Y1 receptor model.
