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

Adrienn Monika Szabo, Tamas Erdei, Gabor Viczjan, Rita Kiss, Judit Zsuga, C. Papp, Akos Pinter, B. Juhász, Z. Szilvássy, R. Gesztelyi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number2207
JournalMolecules
Volume24
Issue number12
DOIs
Publication statusPublished - Jun 12 2019

Fingerprint

Adenosine A1 Receptor Antagonists
guinea pigs
adenosines
nucleosides
Nucleosides
Computer Simulation
inhibitors
Guinea Pigs
Adenosine
interactions
Adenosine A1 Receptor Agonists
interference
Heart Atria
curves
4-nitrobenzylthioinosine
pretreatment
enzymes
interstitials
Fluxes
Enzymes

Keywords

  • A1 adenosine receptor
  • Adenosine
  • Computer simulation
  • CPA
  • FSCPX
  • NBTI
  • Operational model of agonism
  • Receptorial responsiveness method
  • RRM

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

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. / Szabo, Adrienn Monika; Erdei, Tamas; Viczjan, Gabor; Kiss, Rita; Zsuga, Judit; Papp, C.; Pinter, Akos; Juhász, B.; Szilvássy, Z.; Gesztelyi, R.

In: Molecules, Vol. 24, No. 12, 2207, 12.06.2019.

Research output: Contribution to journalArticle

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AU - Kiss, Rita

AU - Zsuga, Judit

AU - Papp, C.

AU - Pinter, Akos

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AU - Szilvássy, Z.

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