Characterization of 'Mini-Nucleotides' as P2X Receptor Agonists in Rat Cardiomyocyte Cultures. An Integrated Synthetic, Biochemical, and Theoretical Study
| Autor: | Tova Zinman, Bilha Fischer, Irit Rutman-Halili, Asher Shainberg, Revital Yefidoff, Kenneth A. Jacobson, Dan Thomas Major, Valadimir Shneyvays |
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| Rok vydání: | 1999 |
| Předmět: |
Models
Molecular Purinergic P2 Receptor Agonists Agonist medicine.drug_class chemistry.chemical_element Calcium Crystallography X-Ray Ligands Contractility Structure-Activity Relationship Drug Discovery medicine Animals Myocyte Nucleotide Receptor Cells Cultured chemistry.chemical_classification Chemistry Myocardium Myocardial Contraction Organophosphates In vitro Rats Biochemistry Biological target Xanthines Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 42:2685-2696 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm990085i |
| Popis: | The design and synthesis of "mini-nucleotides", based on a xanthine-alkyl phosphate scaffold, are described. The physiological effects of the new compounds were evaluated in rat cardiac cell culture regarding Ca(2+) elevation and contractility. The results indicate biochemical and physiological profiles similar to those of ATP, although at higher concentrations. The biological target molecules of these "mini-nucleotides" were identified by using selective P2-R and A(1)-R antagonists and P2-R subtype selective agonists. On the basis of these results and of experiments in Ca(2+) free medium, in which [Ca(2+)](i) elevation was not observed, we concluded that interaction of the analogues is likely with P2X receptor subtypes, which causes Ca(2+) influx. Theoretical calculations analyzing electronic effects within the series of xanthine-alkyl phosphates were performed on reduced models at quantum mechanical levels. Calculated dipole moment vectors, electrostatic potential maps, and volume parameters suggest an explanation for the activity or inactivity of the synthesized derivatives and predict a putative binding site environment for the active agonists. Xanthine-alkyl phosphate analogues proved to be selective agents for activation of P2X-R subtypes, whereas ATP activated all P2-R subtypes in cardiac cells. Therefore, these analogues may serve as prototypes of selective drugs aiming at cardiac disorders mediated through P2X receptors. |
| Databáze: | OpenAIRE |
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