UK 432097 / Pfizer - LARVOL DELTA

Crystal structure of a constitutive active mutant of adenosine A receptor. (PubMed, IUCrJ) - "To reveal the molecular mechanism of mutation-induced constitutive activity, we determined the structure of a typical mutant I92N complexed with the agonist UK-432097...Science, 332, 322-327 ▸], molecular dynamics simulations suggest that the I92N mutant stabilizes the metastable intermediate state through the hydrophilic interaction network and favors the conformational transition of the receptor towards the active state. This research provides a structural template towards the special pharmacological outcome triggered by conformational mutation and sheds light on future structural or pharmaco-logical studies among class A GPCRs."

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A2 receptor agonists and P2Y receptor antagonists modulate expression of thrombospondin-1 (TSP-1) and its secretion from Human Microvascular Endothelial Cells (HMEC-1). (PubMed, Microvasc Res) - "The article presents evidence which proves that the purinoceptor-dependent concept is associated with TSP-1 changes in endothelial cells (EC). Moreover, Human Microvascular Endothelial Cells treatment applied together with agonists (MRE0094 or UK-432,097) and P2Y12R antagonist did not result in any synergistic effect, implicating a possible crosstalk between G proteins in GPCRs dependent signaling. Therefore, we suggest that understanding of the specific mechanism underlying TSP-1 alterations in EC in the context of the dual purinoceptor-dependent approach is essential for antiplatelet therapies and should be the subject of future research."

Journal • THBS1

Binding of adenosine derivatives to carrier proteins may reduce their antiplatelet activity. (PubMed, Biochem Pharmacol) - "Surface plasmon resonance was employed together with molecular docking study to determine the binding kinetics of four selected ARagonists (PSB0777, Cl-Ado, MRE0094, UK432097) to several carrier proteins and to clarify the nature of these interactions...In addition, HSA was shown to significantly reduce the effectiveness of PSB0777 in inhibiting ADP-induced platelet activation. In conclusion, HSA and lipoproteins are important carriers for ARagonists, which can affect pharmacodynamics of ARagonists used as platelet inhibitors."

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Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches. (PubMed, Molecules) - "For the search for AAR agonists, the UK-432097 and a set of 20 compounds available in the BindingDB database were studied. Moreover, they had satisfactory docking and molecular dynamics results compared to those obtained for Regadenoson (Lexiscan), used as the positive control. These compounds can be used in biological assays (in vitro and in vivo) in order to confirm the potential activity agonist to AAR."

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