Summary
5-HT4 receptors have recently been discovered in brain (foetal mice neurons, adult guinea pig hippocampus) and also in guinea pig ileum and ascending colon, rat oesophagus, pig and human heart. These 5-HT4 receptors have been shown to stimulate cAMP production in brain and heart and to inhibit voltage-dependent K+ channels in colliculi neurons.
The pharmacological characteristics of 5-HT4 receptors are very particular. Indole derivatives, including 5 substituted tryptamine agonists, are generally active (especially 5-methoxytryptamine, 5-carboxamidotryptamine, RU 28253). All the 2-methoxy-4-amino-5-chloro substituted benzamide derivatives tested so far, are agonists as are the azabicycloalkylbenzimidazolone derivatives. Classical pharmacological criteria indicate that indole, benzamides and azabicycloalkylbenzimidazolone derivatives act on the same receptor molecule entity. However, [3H]-renzapride (benzamide) binding sites on colliculi membranes are not displaced by indole derivatives including 5-HT, 5-methoxytryptamine and RU 28253. This indicates that either [3H]-renzapride binding sites are unrelated to 5-HT4 receptors or that benzamides and indole derivatives interact at different subsites of the 5-HT4 receptor. The only 5-HT4 receptor antagonist described to date is ICS 205 930 (a competitive antagonist). The affinity of this drug is far lower (μM) than its affinity for 5-HT3 receptors (nM). Finally, another particularity of the 5-HT4 rceptor is its rapid desensitization.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Baxter, G. S., and Clarke, D. E. (1990). Putative 5-HT4 receptors mediate relaxation of rat oesophagus. Abstract of the second IUPHAR satellite meeting on Serotonin 11–13 July, Basel. p. 85.
Bockaert, J., Gabrion, J., Sladeczek, F., Pin, J. P., Récasens, M., Sebben, M., Kemp, D. E., Dumuis, A., and Weiss, S. (1986). Primary culture of striatal neurons: a model of choice for pharmacological and biochemical studies of neurotransmitter receptors. J. Physiol. 81: 219 – 227.
Bockaert, J., Sebben, M., and Dumuis, A. (1990). Pharmacological characterization of 5-hydroxytryptamine4 (5-HT4) receptors positively coupled to adenylate cyclase in adult guinea pig hippocampal membranes: Effect of substituted benzamide derivatives. Mol. Pharmacol. 37: 408–411.
Buchheit, K. H., Engel, G., Muschler, E., and Richardson, B. P. (1985). Study of the contractile effect of 5-hydroxytryptamine (5-HT) in the isolated longitudinal muscle strip from guinea pig ileum. Evidence for two distinct release mechanisms. Naunyn-Schmiedeberg’s Arch. Pharmacol. 329: 36–41.
Chaput, Y., Araneda, R. C., and Andrade, R. (1990). Pharmacological and functional analysis of a novel serotonin receptor in rat hippocampus. Eur. J. Pharmacol. 182: 441–456.
Clarke, D. E., Craig, D. A., and Fozard, J. R. (1989). The 5-HT4 receptor: naughty but nice. Trends Pharmacol. Sci., 10: 385–386.
Craig, D. A., and Clarke. D. E. (1990). Pharmacological characterisation of neuronal receptor for 5-hydroxytryptamine in guinea pig ileum with properties similar to the 5-HT4 receptor. J. Pharmacol. Exp. Ther. 252: 1378–1386.
Craig, D. A., Eglen, R. M., Walsh, L. K. M., Perkins, L. A., Whiting, R. L., and Clarke, D. E. (1990). 5-Methoxytryptamine and 2-methyl-5-hydroxytryptamine induced desensitization as a discriminative tool for the 5-HT3 and putative 5-HT4 receptors in guinea pig ileum. Naunyn-Schmiedeberg’s Arch. Pharmacol. 342: 9–16.
Deterre, P., Paupardin-Tritsch, D., Bockaert, J., and Gerschenfeld, H. M. (1982). cAMP-mediated decrease in K+ conductance evoked by serotonin and dopamine in the same neuron: A biochemical and physiological single cell study. Proc. Natl. Acad. Sci. USA 79: 7934–7938.
Dumuis, A., Bouhelal, R., Sebben, M., Cory, R., and Bockaert, J. (1988). A non-classical 5-hydroxytryptamine receptor positively coupled with adenylate cyclase in the central nervous system. Mol. Pharmacol. 34: 880–887.
Dumuis, A., Sebben, M., and Bockaert, J. (1989a). BRL 24924: a potent agonist at a non classical 5-HT receptor positively coupled with adenylate cyclase in colliculi neurons. Eur. J. Pharmacol. 162: 381–384.
Dumuis, A., Sebben, M., and Bockaert, J. (1989b). The gastrointestinal prokinetic benzamine derivatives are agonists at the non-classical 5-HT receptor (5-HT4) positively coupled to adenylate cyclase in neurons. Naunyn Schmiedeberg's Arch. Pharmacol. 340: 403–410.
Dumuis, A., Schuurkes, J., Ghoos, E., Sebben, M., and Bockaert, J. (1990a) Comparison between the potencies of a series of benzamide derivatives which stimulate 5-HT4 receptors of mouse colliculi neurons and guinea-pig ileum (submitted for publication).
Dumuis, A., Sebben, M., Monferini, E., Nicola, M., Ladinski, H., and Bockaert, J. (1990b). Benzimidazolone derivatives as a novel class of potent agonists at the 5-HT4 receptor positively coupled to adenylate cyclase in brain. Abstract of second IUPHAR satellite meeting on Serotonin 14–13 July, Basel. p. 42.
Dumuis, A., Sebben, M., Monferini, E., Nicola, M., Turconi, M., Ladinski, H., and Bockaert, J. (1991). Azabicycloalkylbenzimidazolone derivatives as a novel class of potent agonists at the 5-HT4 receptor coupled to adenylate cyclase in brain. Naunyn Schmiedeberg's Arch. Pharmacol. 343: 245–251.
Elswood, C. J., Bunce, K. T., and Humphrey, P. P. A. (1990). Identification of 5-HT4 receptors in guinea-pig ascending colon. Abstract of the second IUPHAR satellite meeting on Serotonin 11–13 July, Basel p. 86.
Fozard, J. R. (1990). Agonists and antagonists of 5-HT3 receptors. In: Saxena, P. R., Wallis, D. I., Wouters, W., and Bevan, P. (eds). Cardiovascular Pharmacology of 5-hydroxytryptamine. Kluwer Academic Publishers, Dordrecht, pp. 101 – 115.
Hamill, P. O., Marty, A., Neher, E., Sackmann, B., and Sigworth, F. K. (1981). Improved patch-clamp techniques for high resolution current recording from cells and cell-free membrane patches. Pflügers Arch. 391: 85 – 100.
Johnson, J. W., and Ascher, P. (1987). Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature. 325: 529 – 531.
Kandel, E. R., and Schwartz, J. H. (1982). Molecular biology of learning: modulation of transmitter release. Science. 218: 433 – 443.
Kaumann, A. J., Sanders, L., Brown, A. M., Murray, K. J., and Brown, M. J. (1990a). A 5-hydroxytryptamine receptor in human atrium. Br. J. Pharmacol. 100: 879–885.
Kaumann, A. J., Sanders, L., Brown, A. M., Murray, K. J., and Brown, M. J. (1990b). 5-HT and the human heart. Abstract of the Second IUPHAR satellite meeting on Serotonin 11–13 July, Basel. p. 141.
Richardson, B. P., Engel, G., Donatsch, P., and Stadler, P. A. (1985). Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature 316: 126 – 131.
Rizzi, C. A., Onori, L., Sanguini, A. M., Coccini, T., and Tonini, M. (1990). Facilitation of cholinergic transmission and peristalsis induced by a novel class of benzimidazolone derivatives in the guinea-pig small intestine. Abstract of the second IUPHAR satellite meeting on serotonin 1l–13 July, Basel p. 152.
Sanger, G. J. (1987). Increased gut cholinergic activity and antagonism of 5-hydroxytryptamine M-receptors by BRL 24924: potential clinical importance of BRL 24924. Br. J. Pharmacol. 91: 77–87.
Turconi, M., Nicola, M., Quintero, M. G., Maiocchi, L., Micheletti, R., Giraldo, E., and Donetti, A. (1990). Synthesis of a new class of 2,3-dihydro-2-oxo-IH-benzimidazolone-1carboxylic acid derivatives as highly potent 5-HT3 receptor antagonists. J. Med. Chem. 33: 2101–2108.
Villalòn, C. M., den Boer, M. O., Heiligers, J. P. C., and Saxena, P. R. (1990). Mediation of 5-hydroxytryptamine-induced tachycardia in the pig by the putative 5-HT,. Br. J. Pharmacol. 100: 665–667.
Weiss, S., Sebben, M., Garcia-Sainz, A. J., and Bockaert, J. (1985). D2-dopamine receptor-mediated inhibition of cyclic AMP formation in striatal neurons in primary culture. Mol. Pharmacol. 27: 595–599.
Weiss, S., Pin, J.-P., Sebben, M., Kemp, D. E., Sladeczeck, F., Gabrion, J., and Bockaert, J. (1986). Synaptogenesis of cultured striatal neurons in serum-free medium: A morphological and biochemical study. Proc. Natl. Acad. Sci. USA 83: 2238–2242.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1991 Birkhäuser Verlag Basel/Switzerland
About this chapter
Cite this chapter
Bockaert, J., Fagni, L., Sebben, M., Dumuis, A. (1991). Pharmacological Characterization of Brain 5-HT4 Receptors: Relationship between the Effects of Indole, Benzamide and Azabicycloalkybenzimidazolone Derivatives. In: Fozard, J.R., Saxena, P.R. (eds) Serotonin: Molecular Biology, Receptors and Functional Effects. Birkhäuser Basel. https://doi.org/10.1007/978-3-0348-7259-1_20
Download citation
DOI: https://doi.org/10.1007/978-3-0348-7259-1_20
Publisher Name: Birkhäuser Basel
Print ISBN: 978-3-0348-7261-4
Online ISBN: 978-3-0348-7259-1
eBook Packages: Springer Book Archive