Methodical challenges and a possible resolution in the assessment of receptor reserve for adenosine, an agonist with short half-life

Judit Zsuga, Tamas Erdei, Katalin Szabó, Nora Lampe, C. Papp, Akos Pinter, Andras Jozsef Szentmiklosi, B. Juhász, Z. Szilvássy, R. Gesztelyi

Research output: Article

3 Citations (Scopus)

Abstract

The term receptor reserve, first introduced and used in the traditional receptor theory, is an integrative measure of response-inducing ability of the interaction between an agonist and a receptor system (consisting of a receptor and its downstream signaling). The underlying phenomenon, i.e., stimulation of a submaximal fraction of receptors can apparently elicit the maximal effect (in certain cases), provides an opportunity to assess the receptor reserve. However, determining receptor reserve is challenging for agonists with short half-lives, such as adenosine. Although adenosine metabolism can be inhibited several ways (in order to prevent the rapid elimination of adenosine administered to construct concentration-effect (E/c) curves for the determination), the consequent accumulation of endogenous adenosine biases the results. To address this problem, we previously proposed a method, by means of which this bias can be mathematically corrected (utilizing a traditional receptor theory-independent approach). In the present investigation, we have offered in silico validation of this method by simulating E/c curves with the use of the operational model of agonism and then by evaluating them using our method. We have found that our method is suitable to reliably assess the receptor reserve for adenosine in our recently published experimental setting, suggesting that it may be capable for a qualitative determination of receptor reserve for rapidly eliminating agonists in general. In addition, we have disclosed a possible interference between FSCPX (8-cyclopentyl-N3-[3-(4-(fluorosulfonyl)benzoyloxy)propyl]-N1-propylxanthine), an irreversible A1 adenosine receptor antagonist, and NBTI (S-(2-hydroxy-5-nitrobenzyl)-6-thioinosine), a nucleoside transport inhibitor, i.e., FSCPX may blunt the effect of NBTI.

Original languageEnglish
Article number839
JournalMolecules
Volume22
Issue number5
DOIs
Publication statusPublished - máj. 1 2017

Fingerprint

Purinergic P1 Receptor Agonists
adenosines
half life
Adenosine
Half-Life
Adenosine A1 Receptor Antagonists
Purinergic P1 Receptors
Nucleosides
Computer Simulation
Metabolism
nucleosides
metabolism
curves
stimulation
inhibitors
elimination
4-nitrobenzylthioinosine

ASJC Scopus subject areas

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

Cite this

Methodical challenges and a possible resolution in the assessment of receptor reserve for adenosine, an agonist with short half-life. / Zsuga, Judit; Erdei, Tamas; Szabó, Katalin; Lampe, Nora; Papp, C.; Pinter, Akos; Szentmiklosi, Andras Jozsef; Juhász, B.; Szilvássy, Z.; Gesztelyi, R.

In: Molecules, Vol. 22, No. 5, 839, 01.05.2017.

Research output: Article

Zsuga, Judit ; Erdei, Tamas ; Szabó, Katalin ; Lampe, Nora ; Papp, C. ; Pinter, Akos ; Szentmiklosi, Andras Jozsef ; Juhász, B. ; Szilvássy, Z. ; Gesztelyi, R. / Methodical challenges and a possible resolution in the assessment of receptor reserve for adenosine, an agonist with short half-life. In: Molecules. 2017 ; Vol. 22, No. 5.
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abstract = "The term receptor reserve, first introduced and used in the traditional receptor theory, is an integrative measure of response-inducing ability of the interaction between an agonist and a receptor system (consisting of a receptor and its downstream signaling). The underlying phenomenon, i.e., stimulation of a submaximal fraction of receptors can apparently elicit the maximal effect (in certain cases), provides an opportunity to assess the receptor reserve. However, determining receptor reserve is challenging for agonists with short half-lives, such as adenosine. Although adenosine metabolism can be inhibited several ways (in order to prevent the rapid elimination of adenosine administered to construct concentration-effect (E/c) curves for the determination), the consequent accumulation of endogenous adenosine biases the results. To address this problem, we previously proposed a method, by means of which this bias can be mathematically corrected (utilizing a traditional receptor theory-independent approach). In the present investigation, we have offered in silico validation of this method by simulating E/c curves with the use of the operational model of agonism and then by evaluating them using our method. We have found that our method is suitable to reliably assess the receptor reserve for adenosine in our recently published experimental setting, suggesting that it may be capable for a qualitative determination of receptor reserve for rapidly eliminating agonists in general. In addition, we have disclosed a possible interference between FSCPX (8-cyclopentyl-N3-[3-(4-(fluorosulfonyl)benzoyloxy)propyl]-N1-propylxanthine), an irreversible A1 adenosine receptor antagonist, and NBTI (S-(2-hydroxy-5-nitrobenzyl)-6-thioinosine), a nucleoside transport inhibitor, i.e., FSCPX may blunt the effect of NBTI.",
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AU - Lampe, Nora

AU - Papp, C.

AU - Pinter, Akos

AU - Szentmiklosi, Andras Jozsef

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AU - Szilvássy, Z.

AU - Gesztelyi, R.

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