Characterisation of the effects of SR146131, a novel non-peptide CCK(1) receptor agonist, on IMR-32 human neuroblastoma cells

The effect of ¿2-[4-(4-chloro-2, 5-dimethoxy-phenyl)-5-[2-cyclohexyl-ethyl)-thiazol-2-ylcarbamoy l]-5, 7-dimethyl-indol-1-yl¿-acetic acid (SR146131), a novel non-peptide agonist of cholecystokinin (CCK) CCK(1) receptors, was compared to the effect of sulphated cholecystokinin octapeptide (CCK-8-S) o...

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Published in:European journal of pharmacology 2000-06, Vol.397 (2-3), p.303-310
Main Authors: Schaeffer, P, Nestor, A L, Prabonnaud, V, Bachy, A, Laplace, M C, Keane, P E, Bignon, E, Herbert, J M
Format: Article
Language:English
Subjects:
Benzodiazepinones - pharmacology
Binding, Competitive - drug effects
Calcium - metabolism
Devazepide - pharmacology
Dose-Response Relationship, Drug
Humans
Indoles - pharmacology
Iodine Radioisotopes
Neuroblastoma - metabolism
Neuroblastoma - pathology
Phenylurea Compounds - pharmacology
Phosphatidylinositols - metabolism
Radioligand Assay
Receptors, Cholecystokinin - agonists
Receptors, Cholecystokinin - antagonists & inhibitors
Sincalide - analogs & derivatives
Sincalide - metabolism
Sincalide - pharmacology
Thiazoles - pharmacology
Tumor Cells, Cultured
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Summary:The effect of ¿2-[4-(4-chloro-2, 5-dimethoxy-phenyl)-5-[2-cyclohexyl-ethyl)-thiazol-2-ylcarbamoy l]-5, 7-dimethyl-indol-1-yl¿-acetic acid (SR146131), a novel non-peptide agonist of cholecystokinin (CCK) CCK(1) receptors, was compared to the effect of sulphated cholecystokinin octapeptide (CCK-8-S) on CCK(1) receptors of the human neuroblastoma cell line IMR-32. SR146131 inhibited [125I]CCK-8-S binding to IMR-32 cells at nanomolar concentrations. SR146131 and CCK-8-S increased intracellular free Ca(2+) levels ([Ca(2+)](i)) in the same concentration range (EC(50)=6+/-2.3 and 1.3+/-0.14 nM, respectively). Although the shape of the [Ca(2+)](i) increase induced by CCK-8-S and SR146131 was slightly different, extracellular Ca(2+) removal affected the response of both compounds to a similar degree, and the response of both compounds was essentially due to Ca(2+) release from intracellular stores. This was also confirmed by measuring the [Ca(2+)](i) response of single cells: both compounds induced [Ca(2+)](i) oscillations at subnanomolar concentrations and elicited a large peak increase in [Ca(2+)](i) at higher concentrations (EC(50)=0.5+/-0.04 and 5.7+/-1.9 nM for CCK-8-S and SR146131, respectively). Both CCK-8-S and SR146131 induced a sustained increase of phosphoinositide turnover in these cells, and acted at similar concentrations (EC(50)=2.7+/-0.7 and 6+/-3.1 nM, respectively), although the maximal effect of SR146131 was somewhat lower than the effect of CCK-8-S. These data show that SR146131 activates human CCK(1) receptors on IMR-32 cells in a manner and with a potency similar to that of CCK-8-S.
ISSN:0014-2999