Zsuga Judit, Erdei Tamas, Szabó Katalin, Lampe Nora, Papp Csaba, Pinter Akos, Szentmiklosi Andras Jozsef, Juhasz Bela, Szilvássy Zoltán, Gesztelyi Rudolf
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.
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
Molecules. 2017 May 19;22(5):839. doi: 10.3390/molecules22050839.
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--[3-(4-(fluorosulfonyl)benzoyloxy)propyl]-¹-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.
“受体储备”这一术语最早在传统受体理论中提出并使用，是对激动剂与受体系统（由受体及其下游信号传导组成）之间相互作用的反应诱导能力的综合度量。其潜在现象，即刺激不到半数的受体显然就能引发最大效应（在某些情况下），为评估受体储备提供了契机。然而，对于半衰期较短的激动剂（如腺苷）而言，确定受体储备颇具挑战性。尽管可以通过多种方式抑制腺苷代谢（以防止为构建浓度 - 效应（E/c）曲线而给予的腺苷快速消除），但内源性腺苷的随之积累会使结果产生偏差。为解决这一问题，我们之前提出了一种方法，通过该方法可以在数学上校正这种偏差（采用一种与传统受体理论无关的方法）。在本研究中，我们通过使用激动作用的操作模型模拟E/c曲线，然后用我们的方法对其进行评估，从而对该方法进行了计算机模拟验证。我们发现，在我们最近发表的实验环境中，我们的方法适用于可靠地评估腺苷的受体储备，这表明它总体上可能有能力对快速消除的激动剂的受体储备进行定性测定。此外，我们还揭示了不可逆的A₁腺苷受体拮抗剂FSCPX（8 - 环戊基 - - [3 - (4 - (氟磺酰基)苯甲酰氧基)丙基] - ¹ - 丙基黄嘌呤）与核苷转运抑制剂NBTI（S - (2 - 羟基 - 5 - 硝基苄基) - 6 - 硫代肌苷）之间可能存在的干扰，即FSCPX可能会减弱NBTI的作用。
