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Molecules 2017, 22(5), 839; doi:10.3390/molecules22050839

Methodical Challenges and a Possible Resolution in the Assessment of Receptor Reserve for Adenosine, an Agonist with Short Half-Life

1
Department of Health Systems Management and Quality Management for Health Care, Faculty of Public Health, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary
2
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary
3
Institute of Mathematics, Faculty of Science and Technology, University of Debrecen, Egyetem ter 1, H-4032 Debrecen, Hungary
*
Author to whom correspondence should be addressed.
Academic Editors: Francisco Ciruela and Eddy Sotelo
Received: 31 March 2017 / Revised: 5 May 2017 / Accepted: 15 May 2017 / Published: 19 May 2017
(This article belongs to the Special Issue Adenosine Receptors)
View Full-Text   |   Download PDF [963 KB, uploaded 19 May 2017]   |  

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. View Full-Text
Keywords: adenosine; CPA; FSCPX; NBTI; A1 adenosine receptor; receptor reserve; receptorial responsiveness method; RRM adenosine; CPA; FSCPX; NBTI; A1 adenosine receptor; receptor reserve; receptorial responsiveness method; RRM
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Zsuga, J.; Erdei, T.; Szabó, K.; Lampe, N.; Papp, C.; Pinter, A.; Szentmiklosi, A.J.; Juhasz, 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. Molecules 2017, 22, 839.

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