Abstract
Binding studies indicate that both serotonin and dopamine receptors are involved in the mechanism of action of neuroleptic drugs (Leysen et al., 1978), and have distinguished between two 5-HT binding sites, labelled with high affinity either by [3H]-serotonin (5-HT1) or by [3H]-spiperone in the frontal cortex (5-HT2) in various brain tissues (Peroutka and Snyder, 1979). Structural modification of these molecules with neuroleptic properties led to the synthesis of a number of quinazolinedione derivatives. These substances prevented formation of gastric ulcers in rats challenged with compound 48/80 (which induces release of both histamine and serotonin from mast cells); these findings indicated inhibition of serotonin activity, since these rats were protected against histamine-induced effects by treatment with antihistaminic drugs (Awouters et al., 1982). The ability of this group of molecules and of a number of known serotonin antagonists to block serotonin-induced contractions was determined on the isolated caudal artery of the rat (Van Nueten et al., 1981). Their activities correlated significantly with their affinities for 5-HT2 receptors, as measured in radioligand binding studies (Leysen et al., 1982). Of these 5-HT2 receptor antagonists, ketanserin (R 41 468; 3-[2-[4-(p-fluorobenzoyl)-piperidino]ethyl]-2,4(1H,3H)-quinazolinedione) emerged as being the most selective for 5-HT2 receptor sites (Leysen et al., 1981; Van Nueten and Vanhoutte, 1981). It inhibited serotonin-induced contraction of isolated blood vessels (Van Nueten et al., 1981).
Presented by J. M. Van Nueten.
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
Ahlund, L., Lundgren, Y., Sjoberg, B. and Weiss, L. (1977). Vascular reactivity to 5-hydroxytryptamine (5-HT) in hindquarter vascular beds, aortic strips and portal veins from spontaneously hypertensive and normotensive rats. Acta Physiol. Scand., 101, 489–492
Ashton, J. H., Benedict, C. R., Fitzgerald, C., Raheja, S., Taylor, A., Campbell, W. B., Buja, L. M. and Willerson, J. T. (1986). Serotonin as a mediator of cyclic flow variations in stenosed canine coronary arteries. Circulation, 73, 572–578
Awouters, F., Leysen, J. E., De Clerck, F. and Van Nueten, J. M. (1982). General pharmacological profile of ketanserin (R 41 468), a selective 5-HT2 receptor antagonist. In De Clerck, F. and Vanhoutte, P. M. (Eds), 5-Hydroxytryptamine in Peripheral Reactions, Raven Press, New York, pp. 193–197
Awouters, F., Niemegeers, C. J. E. and Janssen, P. A. J.(1985). A pharmacological analysis of the rat mast cell 5-HT gastric ulcer test and the effects of ketanserin. Drug Devel Res., 5, 303–312
Cocks, T. M. and Angus, J. A. (1983). Endothelium dependent relaxation of coronary arteries by noradrenaline and serotonin. Nature, 305, 627–630
Cohen, R. A. (1985). Serotonergic prejunctional inhibition of canine coronary adrenergic nerves. J. Pharmacol. Exp. Ther., 235, 76–80
Cohen, R. A., Shepherd, J. T. and Vanhoutte, P. M. (1983). 5-Hydroxytryptamine can mediate endothelium-dependent relaxation of coronary arteries. Am. J. Physiol., 245, H1077–H1080
Collis, M. G. and Vanhoutte, P. M. (1977). Vascular reactivity of isolated perfused kidneys from male and female spontaneously hypertensive rats. Circ. Res., 41, 759–767
De Clerck, F. and Herman, A. G. (1983). 5-Hydroxytryptamine and platelet aggregation. Fed. Proc., 42, 228–232
De Clerck, F. and Van Nueten, J. M. (1982). Platelet-mediated vascular contractions: inhibition of the serotonergic component by ketanserin. Thromb. Res., 27, 713–121
De Clerck, F., David, J. L. and Janssen, P. A. J. (1982). Inhibition of 5-hydroxytryptamine-induced and amplified human platelet aggregation by ketanserin (R 41 468), a selective 5-HT2 receptor antagonist. Agents Actions, 12, 388–397
De Clerck, F., Xhonneux, B., Leysen, J. and Janssen, P. A. J. (1984). The involvement of 5-HT2-receptor Sites in the activation of cat platelets. Thromb. Res., 33, 305–321
De Crée, J., Leempoels, J., De Cock, W., Geukens, H. and Verhaegen, H. (1981). The antihypertensive effects of a pure and selective serotonin-receptor blocking agent (R 41 468) in elderly patients. Angiology, 32, 137–144
De Crée, J., Leempoels, J., Demoen, B., Roels, V. and Verhaegen, H. (1985a). The effect of ketanserin, a 5-HT2-receptor antagonist on 5-hydroxytryptamine-induced irreversible platelet aggregation in patients with cardiovascular diseases. Agents Actions, 16, 313–317
De Crée, J., Hoing, M., De Ryck, M. and Symoens, J. (1985b). The acute antihypertensive effect of ketanserin increases with age. J. Cardiovasc. Pharmacol., 7, S126–S127
de la Lande, I. S., Cannell, V. A. and Waterson, J. G. (1966). The interaction of serotonin and noradrenaline on the perfused artery. Br. J. Pharmacol. Chemother., 28, 255–272
De Mey, C. and Vanhoutte, P. M. (1981). Effect of age and spontaneous hypertension on the tachyphylaxis to 5-hydroxytryptamine and angiotensin II in the isolated rat kidney. Hypertension, 3, 718–724
Doyle, A. E., Fraser, J. R. E. and Marshall, R. J. (1959). Reactivity of forearm vessels to vasoconstrictor substances in hypertensive and normotensive subjects. Clin. Sci., 18, 441–54
Engel, G., Göthert, M., Müller-Schweinitzer, E., Schlicker, E., Sistonen, L. and Stadler, P. A. (1983). Evidence for common pharmacological properties of [3H] 5-hydroxytryptamine binding sites, presynaptic 5-hydroxytryptamine autorecep-tors in CNS and inhibitory presynaptic 5-hydroxytryptamine receptors on sympathetic nerves. Naunyn-Schmiedeberg’s Arch. Pharmacol., 324, 116–124
Furchgott, R. F. (1983). Role of endothelium in the responses of vascular smooth muscle. Circ. Res., 53, 557–573
Houston, D. S., Shepherd, J. T. and Vanhoutte, P. M. (1985). Adenine nucleotides, serotonin and endothelium-dependent relaxations to platelets. Am. J. Physiol., 248, H389–H395
Janssen, P. A. J. (1985). Pharmacology of potent and selective S2-serotonergic antagonists. J. Cardiovasc. Pharmacol., 7, S2–S11
Janssens, W. J. and Van Nueten, J. M. (1986). The direct and amplifying effects of serotonin are increased with age in the isolated perfused kidney of Wistar and spontaneously hypertensive rats. Naunyn-Schmiedeberg’s Arch. Pharmacol., 334, 327–332
Leysen, J. E., Niemegeers, C. J. E., Tollenaere, J. P. and Laduron, P. M. (1978). Serotonergic component of neuroleptic receptors. Nature, 272, 168–171
Leysen, J. E., Awouters, F., Kennis, L., Laduron, P. M., Vandenberk, J. and Janssen, P. A. J. (1981). Receptor binding profile of R 41 468, a novel antagonist at 5-HT2 receptors. Life Sci., 28, 1015–1022
Leysen, J. E., Niemegeers, C. J. E., Van Nueten, J. M. and Laduron, P. M. (1982). [3H] Ketanserin (R 41 468), a selective 3H-ligand for serotonin2 receptor binding sites. Binding properties, brain distribution and functional role. Mol. Pharmacol., 21, 301–314
McGrath, M. A. (1977). 5-Hydroxytryptamine and neurotransmitter release in canine blood vessels. Inhibition by low and augmentation by high concentrations. Circ. Res., 41, 428–435
Myers, J. H., Mecca, T. E. and Webb, R. C. (1985). Direct and sensitizing effects of serotonin agonists and antagonists on vascular smooth muscle. J. Cardiovasc. Pharmacol., 7, S44–S48
Nevelstgen, A., De Clerck, F., Loots, W. and De Gryse, A. (1984). Restoration of post-thrombotic peripheral collateral circulation in the cat by ketanserin, a selective 5-HT2 receptor antagonist. Arch. Int. Pharmacodyn., 270, 268–274
Page, I. H. (1954). Serotonin (5-hydroxytryptamine). Physiol. Rev., 34, 563–588
Peroutka, S. J. and Snyder, S. H. (1979). Multiple serotonin receptors. Differential binding of [3H]-5-hydroxytryptamine, [3H]-lysergic acid diethylamide and [3H]-spiroperidol. Mol. Pharmacol., 16, 687–699
Reyntjens, A., Gelders, Y. G., Hoppenbrouwers, M. J. A. and Vanden Bussche, G. (1986). Thymosthenic effects of ritanserin (R 55 667), a centrally acting serotonin-S2receptor blocker. Drug Devel. Res., 8, 205–212
Robertson, J. I. S., Stott, D. J. and Ball, S. G. (1986). The serotonin antagonist ketanserin in the treatment of clinical hypertension: a short review. J. Hypertension, 4, Suppl. 5, S119–S121
Scroop, G. C. and Walsh, J. A. (1968). Interactions between angiotensin, noradrenaline and serotonin on the peripheral blood vessels in man. Aust. J. Exp. Biol Med. Sci., 46, 573–580
Vanhoutte, P. M. (Ed.) (1985). Serotonin and the Cardiovascular System, Raven Press, New York
Vanhoutte, P. M. (1987). Serotonin and the vascular wall. Int. J. Cardiol, 14, 189–203
Vanhoutte, P. M. and Houston, D. S. (1985). Platelets, endothelium, and vasospasm. Circulation, 72, 728–734
Vanhoutte, P., Amery, A., Birkenhäger, W., Breckenridge, A., Bühler, F., Distler, A., Dormandy, J., Doyle, A., Frohlich, E., Hansson, L., Hedner, Th., Hollenberg, N., Jensen, H.-E., Lund-Johansen, P., Meyer, P., Opie, L., Robertson, J., Safar, M., Schalekamp, M., Symoens, J., Trap-Jensen, J. and Zanchetti, A. (1988). Focus on the effects of ketanserin. Hypertension, 11, 111–133
Van Nueten, J. M. and Janssens, W. J. (1986). Augmentation of vasoconstrictor responses to serotonin by acute and chronic factors: inhibition by ketanserin. Hypertension, 4, S55–S59
Van Nueten, J. M. and Vanhoutte, P. M. (1981). Selectivity of calcium antagonism and serotonin antagonism with respect to venous and arterial tissues. Angiology, 32, 476–484
Van Nueten, J. M., Janssen, P. A. J., Van Beek, J., Xhonneux, R., Verbeuren, T. J. and Vanhoutte, P. M. (1981). Vascular effects of ketanserin (R 41 468), a novel antagonist of 5-HT2 serotonergic receptors. J. Pharmacol. Exp. Ther., 218, 217–230
Van Nueten, J. M., Janssen, P. A. J., De Ridder, W. and Vanhoutte, P. M. (1982). Interaction between 5-hydroxytryptamine and other vasoconstrictor substances in the isolated femoral artery of the rabbit: Effect of ketanserin (R 41 468). Eur. J. Pharmacol., 77, 281–287
Van Nueten, J. M., Janssens, W. J. and Vanhoutte, P. M. (1985). Serotonin and vascular reactivity. Pharmacol Res. Commun., 17, 585–608
Van Nueten, J. M., Janssen, P. A. J., Symoens, J., Janssens, W. J., Heykants, J., De Clerck, F., Leysen, J. E., Vancauteren, H. and Vanhoutte, P. M. (1987). Ketanserin. In Scriabine, A. (Ed.), New Cardiovascular Drugs, Raven Press, New York, pp. 1–56
Van Reempts, J., Borgers, M., Xhonneux, R., De Clerck, F. and Awouters, F. (1981). The inhibition of ischemic lesions of the rat gastric mucosa by a novel serotonin-antagonist: a light and electron microscopic study. Angiology, 32, 529–542
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Copyright information
© 1989 The editors and contributors
About this chapter
Cite this chapter
Nueten, J.M.V., Janssen, P.A.J., Janssens, W.J., Vanhoutte, P.M. (1989). The Development of 5-HT2 Receptor Antagonists. In: Mylecharane, E.J., Angus, J.A., de la Lande, I.S., Humphrey, P.P.A. (eds) Serotonin. Satellite Symposia of the IUPHAR 10th International Congress of Pharmacology. Palgrave Macmillan, London. https://doi.org/10.1007/978-1-349-10114-6_1
Download citation
DOI: https://doi.org/10.1007/978-1-349-10114-6_1
Publisher Name: Palgrave Macmillan, London
Print ISBN: 978-1-349-10116-0
Online ISBN: 978-1-349-10114-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)