Ribose modified nucleosides and nucleotides as ligands for purine receptors

Molecular modeling of receptors for adenosine and nucleotide (P2) receptors with docked ligand, based on mutagenesis, was carried out. Adenosine 3',5' -bisphosphate derivatives act as selective P2Y(1) antagonists/partial agoni sts. The ribose moiety was replaced with carbocyclics, smaller and larger r ings, conformationally constrained rings, and acyclics, producing compounds that retained receptor affinity. Conformational constraints were built int o the ribose rings of nucleoside and nucleotide ligands using the methanoca rba approach, i.e. fused cyclopropane and cyclopentane rings in place of ri bose, suggesting a preference for the Northern (N) conformation among ligan ds for P2Y(1) and A(1) and A(3)ARs.