title: Effect of asymmetry of concentration-response curves on the results obtained by the receptorial responsiveness method (RRM): an in silico study.
abstract: The receptorial responsiveness method (RRM) was proposed to estimate changes in the concentration of an agonist in the microenvironment of its receptor. Usually, this is done by providing the equieffective concentration of another agonist for the same receptor or for a largely overlapping postreceptorial signaling ("test agonist"). The RRM is a special nonlinear regression algorithm to analyze a concentration-response (E/c) curve that represents the simultaneous actions of a single agonist concentration to be estimated and of increasing concentrations of the test agonist. The aim of this study was to explore whether asymmetry of the E/c curve to be analyzed influences the reliability of the RRM. For this purpose, computer simulation was performed by constructing symmetric and asymmetric E/c curves using the operational model of agonism, and then these curves were analyzed with the RRM. To perform the RRM, 2 types of equations were used: one involving the Hill equation, the simplest model of the E/c relationship, and one containing the Richards equation, an advanced model properly handling E/c curve asymmetry. Results of this study indicate that E/c curve asymmetry does not significantly influence the accuracy of the estimates provided by the RRM. Thus, when using the RRM, it is not necessary to replace the Hill equation with the Richards equation to obtain useful estimates. Furthermore, it was found that estimation of a high concentration of a high-efficacy agonist can fail when the RRM is performed with a low-efficacy test agonist in a system characterized by a small operational slope factor.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Debrecen, H-4012 Debrecen, PO Box 8, Hungary.
authors.forename: Maria
authors.initials: M
authors.lastname: Grenczer
authors.forename: Judit
authors.initials: J
authors.lastname: Zsuga
authors.forename: Laszlo
authors.initials: L
authors.lastname: Majoros
authors.forename: Akos
authors.initials: A
authors.lastname: Pinter
authors.forename: Adam
authors.initials: A
authors.lastname: Kemeny-Beke
authors.forename: Bela
authors.initials: B
authors.lastname: Juhasz
authors.forename: Arpad
authors.initials: A
authors.lastname: Tosaki
authors.forename: Rudolf
authors.initials: R
authors.lastname: Gesztelyi
mesh_terms: D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D008954:Models, Biological; D011955:Receptors, Drug / Q000819:agonists*
chemical_list: D011955:Receptors, Drug