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Updated: Aug 11, 2026

Contractility Measurements of Human Uterine Smooth Muscle to Aid Drug Development
Published on: January 26, 2018
Differential effects of 5-hydroxytryptamine4 receptor agonists at gastric versus cardiac receptors: an operational
Joris H De Maeyer1, Nicolaas H Prins, Jan A J Schuurkes
1Heymans Institute of Pharmacology, De Pintelaan 185, 9000 Gent, Belgium. jdmaeyer@prdbe.jnj.com
Abstract:
Quantification of different levels of 5-hydroxytryptamine4 (5-HT4) receptor agonism expression across animal species as well as across organs within the same animal species offers substantial potential for the separation of desired gastrointestinal versus undesired cardiac pharmacological activity of compounds in development. Since a detailed investigation of such properties is lacking to date, we set out to quantify gastric and cardiac effects of 5-HT4 receptor ligands in the pig, a model considered to be representative for the human situation. An in vitro test was developed to study the potentiating effect of 5-HT, prucalopride, tegaserod, R149402 (4-amino-5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid [3-hydroxy-1-(3-methoxy-propyl)-piperidin-4ylmethyl]-amide), and R199715 (4-amino-5-chloro-2,3-dihydro-benzofuran-7-carboxylic acid [3-hydroxy-1-(3-methoxy-propyl)-piperidin-4ylmethyl]-amide) on electrically induced cholinergic contractions in longitudinal muscle strips of the proximal stomach. The results were compared with inotropic and chronotropic effects of these compounds in the electrically paced left atrium and spontaneously beating right atrium, respectively. To quantify the observed tissue-dependent responses, a nonlinear mixed-effects model based on the operational model of agonism was developed and successfully fitted to the data. The model quantified the tissue-dependent partial agonism of the selective 5-HT4 receptor agonists prucalopride, R149402, and R199715, whereas tegaserod and 5-HT were equiefficacious. The model was further extended to incorporate the responses to prucalopride in the presence of the 5-HT4 receptor antagonist GR113808 ([1-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyl-]methyl 1-methyl-1H-indole-3-carboxylate). The results indicate that these interactions do not follow a simple competitive pattern and that they differ between stomach and left atrium.
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