Methodical Challenges and a Possible Resolution in the Assessment of Receptor Reserve for Adenosine, an Agonist with Short Half-Life
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., stimul...
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MDPI AG
2017-05-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/22/5/839 |
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| author | Judit Zsuga Tamas Erdei Katalin Szabó Nora Lampe Csaba Papp Akos Pinter Andras Jozsef Szentmiklosi Bela Juhasz Zoltán Szilvássy Rudolf Gesztelyi |
| author_facet | Judit Zsuga Tamas Erdei Katalin Szabó Nora Lampe Csaba Papp Akos Pinter Andras Jozsef Szentmiklosi Bela Juhasz Zoltán Szilvássy Rudolf Gesztelyi |
| author_sort | Judit Zsuga |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T20:29:35Z |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-11T20:29:35Z |
| publishDate | 2017-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-0913a0d4f2234544ab2e455f475448ac2022-12-22T00:51:50ZengMDPI AGMolecules1420-30492017-05-0122583910.3390/molecules22050839molecules22050839Methodical Challenges and a Possible Resolution in the Assessment of Receptor Reserve for Adenosine, an Agonist with Short Half-LifeJudit Zsuga0Tamas Erdei1Katalin Szabó2Nora Lampe3Csaba Papp4Akos Pinter5Andras Jozsef Szentmiklosi6Bela Juhasz7Zoltán Szilvássy8Rudolf Gesztelyi9Department of Health Systems Management and Quality Management for Health Care, Faculty of Public Health, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, HungaryDepartment of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, HungaryDepartment of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, HungaryDepartment of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, HungaryDepartment of Health Systems Management and Quality Management for Health Care, Faculty of Public Health, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, HungaryInstitute of Mathematics, Faculty of Science and Technology, University of Debrecen, Egyetem ter 1, H-4032 Debrecen, HungaryDepartment of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, HungaryDepartment of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, HungaryDepartment of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, HungaryDepartment of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, HungaryThe 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.http://www.mdpi.com/1420-3049/22/5/839adenosineCPAFSCPXNBTIA1 adenosine receptorreceptor reservereceptorial responsiveness methodRRM |
| spellingShingle | Judit Zsuga Tamas Erdei Katalin Szabó Nora Lampe Csaba Papp Akos Pinter Andras Jozsef Szentmiklosi Bela Juhasz Zoltán Szilvássy Rudolf Gesztelyi Methodical Challenges and a Possible Resolution in the Assessment of Receptor Reserve for Adenosine, an Agonist with Short Half-Life Molecules adenosine CPA FSCPX NBTI A1 adenosine receptor receptor reserve receptorial responsiveness method RRM |
| title | Methodical Challenges and a Possible Resolution in the Assessment of Receptor Reserve for Adenosine, an Agonist with Short Half-Life |
| title_full | Methodical Challenges and a Possible Resolution in the Assessment of Receptor Reserve for Adenosine, an Agonist with Short Half-Life |
| title_fullStr | Methodical Challenges and a Possible Resolution in the Assessment of Receptor Reserve for Adenosine, an Agonist with Short Half-Life |
| title_full_unstemmed | Methodical Challenges and a Possible Resolution in the Assessment of Receptor Reserve for Adenosine, an Agonist with Short Half-Life |
| title_short | Methodical Challenges and a Possible Resolution in the Assessment of Receptor Reserve for Adenosine, an Agonist with Short Half-Life |
| title_sort | methodical challenges and a possible resolution in the assessment of receptor reserve for adenosine an agonist with short half life |
| topic | adenosine CPA FSCPX NBTI A1 adenosine receptor receptor reserve receptorial responsiveness method RRM |
| url | http://www.mdpi.com/1420-3049/22/5/839 |
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