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An Advanced in Silico Modelling of the Interaction between FSCPX, an Irreversible A1 Adenosine Receptor Antagonist, and NBTI, a Nucleoside Transport Inhibitor, in the Guinea Pig Atrium

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Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
2
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
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Department of Health Systems Management and Quality Management for Health Care, Faculty of Public Health, University of Debrecen, H-4032 Debrecen, Hungary
4
Institute of Mathematics, Faculty of Science and Technology, University of Debrecen, H-4032 Debrecen, Hungary
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(12), 2207; https://doi.org/10.3390/molecules24122207
Received: 9 May 2019 / Revised: 6 June 2019 / Accepted: 10 June 2019 / Published: 12 June 2019
(This article belongs to the Section Medicinal Chemistry)
In earlier studies, we generated concentration-response (E/c) curves with CPA (N6-cyclopentyladenosine; a selective A1 adenosine receptor agonist) or adenosine, in the presence or absence of S-(2-hydroxy-5-nitrobenzyl)-6-thioinosine (NBTI, a selective nucleoside transport inhibitor), and with or without a pretreatment with 8-cyclopentyl-N3-[3-(4-(fluorosulfonyl)-benzoyloxy)propyl]-N1-propylxanthine (FSCPX, a chemical known as a selective, irreversible A1 adenosine receptor antagonist), in isolated, paced guinea pig left atria. Meanwhile, we observed a paradoxical phenomenon, i.e., the co-treatment with FSCPX and NBTI appeared to enhance the direct negative inotropic response to adenosine. In the present in silico study, we aimed to reproduce eight of these E/c curves. Four models (and two additional variants of the last model) were constructed, each one representing a set of assumptions, in order to find the model exhibiting the best fit to the ex vivo data, and to gain insight into the paradoxical phenomenon in question. We have obtained in silico evidence for an interference between effects of FSCPX and NBTI upon our ex vivo experimental setting. Regarding the mechanism of this interference, in silico evidence has been gained for the assumption that FSCPX inhibits the effect of NBTI on the level of endogenous (but not exogenous) adenosine. As an explanation, it may be hypothesized that FSCPX inhibits an enzyme participating in the interstitial adenosine formation. In addition, our results suggest that NBTI does not stop the inward adenosine flux in the guinea pig atrium completely. View Full-Text
Keywords: adenosine; CPA; FSCPX; NBTI; A1 adenosine receptor; operational model of agonism; receptorial responsiveness method; RRM; computer simulation adenosine; CPA; FSCPX; NBTI; A1 adenosine receptor; operational model of agonism; receptorial responsiveness method; RRM; computer simulation
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Szabo, A.M.; Erdei, T.; Viczjan, G.; Kiss, R.; Zsuga, J.; Papp, C.; Pinter, A.; Juhasz, B.; Szilvassy, Z.; Gesztelyi, R. An Advanced in Silico Modelling of the Interaction between FSCPX, an Irreversible A1 Adenosine Receptor Antagonist, and NBTI, a Nucleoside Transport Inhibitor, in the Guinea Pig Atrium. Molecules 2019, 24, 2207.

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