Molecular Recognition at Adenine Nucleotide (P2) Receptors in Platelets

ABSTRACT

Transmembrane signaling through P2Y receptors for extracellular nucleotides controls a diverse array of cellular processes, including thrombosis. Selective agonists and antagonists of the two P2Y receptors present on the platelet surface-the G_q-coupled P2Y₁ subtype and the G_i-coupled P2Y₁₂ subtype-are now known. High-affinity antagonists of each have been developed from nucleotide structures. The (N)-methanocarba bisphosphate derivatives MRS2279 and MRS2500 are potent and selective P2Y₁ receptor antagonists. The carbocyclic nucleoside AZD6140 is an uncharged, orally active P2Y₁₂ receptor antagonist of nM affinity. Another nucleotide receptor on the platelet surface, the P2X₁ receptor, the activation of which may also be proaggregatory, especially under conditions of high shear stress, has high-affinity ligands, although high selectivity has not yet been achieved. Although α,β-methylene-adenosine triphosphate (ATP) is the classic agonist for the P2X₁ receptor, where it causes rapid desensitization, the agonist BzATP is among the most potent in activating this subtype. The aromatic sulfonates NF279 and NF449 are potent antagonists of the P2X₁ receptor. The structures of the two platelet P2Y receptors have been modeled, based on a rhodopsin template, to explain the basis for nucleotide recognition within the putative transmembrane binding sites. The P2Y₁ receptor model, especially, has been exploited in the design and optimization of antagonists targeted to interact selectively with that subtype.

KEYWORDS

G protein-coupled receptors - P2Y receptors - agonist - antagonist - mutant

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