A comparison of effects measured with isotonic and isometric recording: II. Concentration‐effect curves for physiological antagonists

Barlow, R. B.; Bond, Susan M.; Grant, Claire; McQueen, Daniel S.; Yaqoob, Zeenat

doi:10.1038/sj.bjp.0704169

Cited by 6 publications

(10 citation statements)

References 10 publications

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“…EC 50 for proscillaridin A in this assay was 2.59 × 10 −8 M. This value is in the range of usual physiological values for neuronal agonists. 32 The Z′ factor calculated for this assay was 0.85 ± 0.01. According to several authors, 33 a Z′ factor >0.5 indicates a statistically reliable separation between positive and negative controls.…”

Section: Resultsmentioning

confidence: 88%

Fluorescent Parkin Cell-Based Assay Development for the Screening of Drugs against Parkinson Disease

et al. 2017

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Parkinson disease (PD) is a prevalent neurodegenerative disease characterized by selective degeneration of dopaminergic neurons in the substantia nigra, causing tremor and motor impairment. Parkin protein, whose mutants are the cause of Parkinson disease type 2 (PARK2), has been mechanistically linked to the regulation of apoptosis and the turnover of damaged mitochondria. Several studies have implicated aberrant mitochondria as a key contributor to the development of PD. In the attempt to discover new drugs, high-content cell-based assays are becoming more important to mimic the nature of biological processes and their diversifications in diseases and will be essential for lead identification and the optimization of therapeutic candidates. We have developed a novel fluorescence cell-based assay for high-content screening to find compounds that can promote the mitochondrial localization of Parkin without severe mitochondrial damage induction. In this work, this model was used to screen a library of 1280 compounds. After the screening campaign, the positive compounds were chosen for further testing, based on the strength of the initial response and lack of cytotoxicity. These results indicated that this Parkin cell-based assay is a robust (Z' > 0.5) and valid strategy to test potential candidates for preclinical studies.

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Section: Resultsmentioning

confidence: 88%

Fluorescent Parkin Cell-Based Assay Development for the Screening of Drugs against Parkinson Disease

et al. 2017

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“…(the second part of (11)) and this response does not depend on the measures C 2 and c 2 of the stimulus S. From (13) it follows that the stimulus S depends on two parameters-c 2 and µ A , and the variable X. The parameter c 2 together with parameters E T m and R (see (12)) define exactly the S-R relations of the tissue and appear to be a receptor property.…”

Section: Using Notations λmentioning

confidence: 96%

“…It needs to be pointed out that µ A is just the relative efficacy e A /C 2 (relative, because the measure unit is C 2 , described in THM-2). In these terms the first equation in (11) can be rewritten as:…”

Section: Using Notations λmentioning

confidence: 99%

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Theoretical Hyperbolic Model of a Partial Agonism: Explicit Formulas for Affinity, Efficacy and Amplification

Milanov¹,

Pencheva²

2012

SJC

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The quantitative analysis of receptor-mediated effect is based on experimental concentration-responsedata in which the independent variable, the concentration of a receptor ligand, is linked with a dependent variable, the biological response. The steps between the drug–receptor interactionand the subsequent biological effect are to some extent unknown.The shape of the fitting curve of the experimental data may give some insights into the nature of the concentration–receptor–response(C-R-R) mechanism. It can be evaluated by non-linear regression analysis of the experimental data points of the independent and dependent variables, which could be considered as a history of the interaction between the drug and receptors. However, this information is not enough to evaluate such important parameters of the mechanism as the dissociation constant (affinity) and efficacy. There are two ways to provide more detailed information about the C-R-R mechanism: (i) an experimental way for obtaining data with new or selective or inactive compounds; and (ii) a theoretical way by making addi-tional assumptions and experimental observations about some elements of the C-R-R mechanism.Using the second way and basic postulates of the so-called occupation theory, a Theoretical Hyperbolic Model (THM) was developed in this study, in order to justify the nature of partial agonism in in-vitro bioassay studies.The model could be used for sensitive analysis of the partial agonist’s behavior from the experimental dose-response data. The explicit formulas derived from the model describe the affinity and relative Stephenson’s efficacy.Moreover, THM allows estimation of the receptor reserve of the almost full agonists under the assumption presented. When the design of the in-vitro bioassay allows assessing the maximal possible effect of a given isolated tissue, the affinity and relative efficacy of the respective partial agonists could be calculated from the experimental dose-response data. It was proved theoretically that the partial agonists have no receptor reserve. This finding confirms experimental results for partial agonists with varying potency. The THM is used further to explain the C-R-R mechanism and to understand more deeply the character of the affinity and efficacy of the agonists by introduction of a new agonist feature called amplification and the parameter amplifier. The THM is compared with other models related with the occupation theory of agonism. The differences and limitations of the application of THM are discussed.

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“…На сьогодні існують значні досягнення в з'ясуванні механізмів (іонних, молекулярних і мембранних) скоротливої активності м'язів, зокрема гладеньких [4][5][6]. Проте вивчення феноменологічних властивостей інтактного ГМ, зокрема кінетичних закономірностей процесу скорочення-розслаблення в ізометричному режимі, залишається вкрай необхідним [1,2,3]. По-перше, від-стеження зміни напруження м'язового препарату в часі робить можливим визначення об'єктивних параметрів скоротливої відповіді (наприклад, амплітуда f m та час t m , за який досягається амплітудне значення сили скорочення, а також швидкості скорочення та розслаблення).…”

Section: була розроблена оптична система реєстрації скорочення гладенunclassified

The optical registration system for isometric contraction of smooth muscle

et al. 2016

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The optical system registration of smooth muscle contraction in isometric mode was developed. Testing of system on smooth muscle strips of rat stomach and caecum was performed. It was tested the possibility of recording optical system spontaneous activity of smooth muscle. The resulting muscle contractions parameters correspond to the literature. Thus designed optical-mechanical method for detecting force and speed can be used for recording isometric contractions of smooth muscles of the stomach and caecum of rats and, therefore, to study the effect of different effectors their mechanokinetic.

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A comparison of effects measured with isotonic and isometric recording: II. Concentration‐effect curves for physiological antagonists

Cited by 6 publications

References 10 publications

Fluorescent Parkin Cell-Based Assay Development for the Screening of Drugs against Parkinson Disease

Fluorescent Parkin Cell-Based Assay Development for the Screening of Drugs against Parkinson Disease

Theoretical Hyperbolic Model of a Partial Agonism: Explicit Formulas for Affinity, Efficacy and Amplification

The optical registration system for isometric contraction of smooth muscle

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