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Platelets contain at least five purinergic G protein-coupled receptors, e.g., the pro-aggregatory P2Y 1 and P2Y 12 receptors, a P2Y 14 receptor (GPR105) of unknown function, and anti-aggregatory A 2A and A 2B adenosine receptor (ARs), in addition to the ligand-gated P2X1 ion channel. Probing the structure-activity relationships (SARs) of the P2X and P2Y receptors for extracellular nucleotides has resulted in numerous new agonist and antagonist ligands. Selective agents derived from known ligands and novel chemotypes can be used to help define the subtypes pharmacologically. Some of these agents have entered into clinical trials in spite of the challenges of drug development for these classes of receptors. The functional architecture of P2 receptors was extensively explored using mutagenesis and molecular modeling, which are useful tools in drug discovery. In general, novel drug delivery methods, prodrug approaches, allosteric modulation, and biased agonism would be desirable to overcome side effects that tend to occur even with receptor subtype-selective ligands. Detailed SAR analyses have been constructed for nucleotide and nonnucleotide ligands at the P2Y 1 , P2Y 12 , and P2Y 14 receptors. The thienopyridine antithrombotic drugs Clopidogrel and Prasugrel require enzymatic pre-activation in vivo and react irreversibly with the P2Y 12 receptor. There is much pharmaceutical development activity aimed at identifying reversible P2Y 12 receptor antagonists. The screening of chemically diverse compound libraries has identified novel chemotypes that act as competitive, non-nucleotide antagonists of the P2Y 1 receptor or the P2Y 12 receptor, and antithrombotic properties of the structurally optimized analogues were demonstrated. In silico screening at the A 2A AR has identified antagonist molecules having novel chemotypes. Fluorescent and other reporter groups incorporated into ligands can enable new technology for receptor assays and imaging. The A 2A agonist CGS21680 and the P2Y 1 receptor antagonist MRS2500 were derivatized for covalent attachment to polyamidoamine dendrimeric carriers of MW 20,000, and the resulting multivalent conjugates inhibited ADP-promoted platelet aggregation. In conclusion, a wide range of new pharmacological tools is available to control platelet function by interacting with cell surface purine receptors.

Activation of a cardiac myocyte P2X4 receptor protects in heart failure. 5’-Phosphonate and 5’-phosphate analogues of AMP containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system could protect from heart failure by potentially activating this cardioprotective channel. Phosphoesters and phosphonodiesters were synthesized and administered in vivo via a mini-osmotic pump in a mouse ischemic heart failure model; most significantly increased intact heart contractile function (echocardiography) compared to vehicle-infusion. Several new thio and deuterated phosphate derivatives were protective in a calsequestrin (CSQ)-overexpressing heart failure model. Diethyl (7, MRS4084) and diisopropyl (8, MRS4074) phosphotriesters were highly protective in the ischemic model. Substitution of 2-Cl with iodo reduced protection in the CSQ model. Diisopropyl ester 16 (MRS2978) of (1’S,2’R,3’S,4’R,5’S)-4’-(6-amino-2-chloropurin-9-yl)-2’,3’-(dihydroxy)-1’-(phosphonoethylene)-bicyclo[3.1.0]hexane was highly efficacious (CSQ), while lower homologue 1’-phosphonomethylene derivative 14 was inactive. Thus, we identified uncharged carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure, suggesting this as a viable and structurally broad approach.