Summary
The mechanism responsible for the antihypertensive effect of urapidil is not yet completely understood. Its vasodilator action has been attributed to an antagonism at vascular α1-adrenoceptors. However, it has been suggested that a central action contributes to the hypotensive effect. Recently, three potent analogues of urapidil have been described which also lower blood pressure by a central mechanism. 5-Hydroxytryptamine (5-HT) receptors of the 5-HT1A subtype have been implicated with the central control of cardiovascular function. In the present study, the affinities of these urapidil derivatives (5-acetyl, 5-formyl- and 5-methylurapidil) for 5-HT receptors were investigated using 3H-8-hydroxy-2-(di-n-propylamino)tetralin (3H-8-OH-DPAT), 125I-iodocyanopindolol (125I-ICYP) and 3H-ketanserin for labelling 5-HT1A, 5-HT1B and 5-HT2 binding sites, respectively. 3H-Prazosin and 3H-clonidine were used as selective α1- and α2-adrenoceptor radioligands, respectively. Urapidil and its analogues produced half-maximum inhibition of 3H-8-OH-DPAT binding at concentrations of 4 × 10−9 mol/l to 4 × 10−7 mol/l with the following order of potency: urapidil < 5-acetyl- < 5-formyl- < 5-methyl-urapidil. Thus, 5-methyl-urapidil is one of the most potent ligands at 5-HT1A recognition sites known to date. The IC50 values of urapidil and its derivatives for 3H-prazosin binding were in the range of 5 × 10−8 mol/l to 8 × 10−7 mol/l (order of potency: urapidil < 5-formyl- < 5-acetyl- ≤ 5-methyl-urapidil). The affinity of these analogues for 5-HT1B, 5-HT2 and α2-adrenergic recognition sites was distinctly lower. Urapidil and its congeners clearly discriminate between 5-HT- and between α-receptor subtypes. It is postulated that the high affinity for 5-HT1A receptors as well as for α1-adrenoceptors is relevant to the hypotensive properties of these compounds.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bevan P, Tulp MThM, Wouters W (1986a) Are 5-HT1A binding sites relevant for the antihypertensive effects of DU 29373? Br J Pharmacol 89:637P
Bevan P, Ramage AG, Wouters W (1986b) Investigation of the effects of DU 29373 on the cardiovascular system of the anaesthetised cat. Br J Pharmacol 89:506P
Bockaert J, Dumuis A, Bouhelal R, Sebben M, Cory RN (1987) Piperazine derivatives including the putative anxiolytic drugs, buspirone and ipsapirone, are agonists at 5-HT1A receptors negatively coupled with adenylate cyclase in hippocampal neurons. Naunyn-Schmiedeberg's Arch Pharmacol 335:588–592
Coote JH, Dalton DW, Feniuk W, Humphrey PPA (1987) The central site of the sympatho-inhibitory action of 5-hydroxytryptamine in the cat. Neuropharmacology 26:147–154
De Vivo M, Maayani S (1986) Characterization of the 5-hydroxytryptamine1A receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes. Naunyn-Schmiedeberg's Arch Pharmacol 335:588–592
Eltze M (1979) Investigations on the mode of action of a new antihypertensive drug, urapidil, in the isolated rat vas deferens. Eur J Pharmacol 59:1–9
Engel G, Göthert M, Hoyer D, Schlicker E, Hillenbrand K (1986) Identity of inhibitory presynaptic 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain cortex with 5-HT1B binding sites. Naunyn-Schmiedeberg's Arch Pharmacol 332:1–7
Fozard JR, Mir AK (1987) Are 5-HT receptors involved in the antihypertensive effects of urapidil? Br J Pharmacol 90:24P
Fozard JR, Mir AK, Middlemiss DN (1987) Cardiovascular response to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in the rat: site of action and pharmacological analysis. J Cardiovasc Pharmacol 9:328–347
Gillis RA, Dretchen KL, Namath I, Anastasi N, Souza JD, Hill K, Browne RK, Quest JA (1987) Hypotensive effect of urapidil: CNS site and relative contribution. J Cardiovasc Pharmacol 9:103–109
Hall MD, El Mestikawy S, Emerit MB, Bichat L, Hamon M, Gozlan H (1985) 3H-8-Hydroxy-2-(di-n-propylamino)tetralin binding to pre- and postsynaptic 5-hydroxytryptamine sites in various regions of the rat brain. J Neurochem 44:1685–1696
Hoyer D, Engel G, Kalkman HO (1985a) Characterization of the 5-HT1B recognition site in rat brain: binding studies with (−)125I-iodocyanopindolol. Eur J Pharmacol 118:1–12
Hoyer D, Engel G, Kalkman HO (1985b) Molecular pharmacology of 5-HT1A and 5-HT2 recognition sites in rat and pig brain membranes: radioligand binding studies with 3H-5-HT, 3H-8-OH-DPAT, (−)125I-iodocyanopindolol, 3H-mesulergine and 3H-ketanserin. Eur J Pharmacol 118:13–23
Kolassa N, Bischler P, Sanders KH (1986) Hypotensive effects of urapidil analogues in cats: peripheral versus central site of action. 11th Scientific Meeting of the International Society of Hypertension, Abstract 0175
Kolassa N, Bischler P, Beller KD, Sanders KH (1987) Inhibition of the hypotensive effect of urapidil and 8-OH-DPAT by the 5-HT receptor antagonist spiroxatrine in cats. Satellite Symp Serotonin, 10th IUPHAR Congress, Abstr 23P
Kuhn DM, Wolf WA, Lovenberg W (1980) Review of the role of the central serotonergic neuronal system in blood pressure regulation. Hypertension 2:243–255
Leysen JE, Niemegeers CJE, van Nueten JM, Laduron PM (1982) 3H-Ketanserin (R41468), a selective 3H-ligand for serotonin2 receptor binding sites. Mol Pharmacol 21:301–314
Markstein R, Hoyer D, Engel G (1986) 5-HT1A-receptors mediate stimulation of adenylate cyclase in rat hippocampus. Naunyn-Schmiedeberg's Arch Pharmacol 333:335–341
McPherson GA (1983) A practical computer based approach to the analysis of radioligand binding experiments. Comp Progr Biomed 17:107–114
Morrow AL, Creese I (1986) Characterization of α1-adrenergic receptor subtypes in rat brain: A reevaluation of 3H-WB4101 and 3H-prazosin binding. Mol Pharmacol 29:321–330
Pazos A, Hoyer D, Palacios JM (1984) The binding of serotonergic ligands to the porcine choroid plexus: Characterization of a new type of serotonin recognition site. Eur J Pharmacol 106:539–546
Sanders KH, Kilian U, Kolassa N, Schoetensack W (1985) Influence of urapidil on α- and β-adrenoceptors in pithed rats. J Anton Pharmacol 5:307–316
Sanders KH, Jurna I (1985) Effects of urapidil, clonidine, prazosin and propranolol on autonomic nerve activity, blood pressure and heart rate in anaesthetized rats and cats. Eur J Pharmacol 110:181–190
Schlegel JR, Peroutka SJ (1986) Nucleotide interactions with 5-HT1A binding sites directly labeled by 3H-8-hydroxy-2-(di-n-propylamino)tetralin (3H-8-OH-DPAT). Biochem Pharmacol 35:1943–1949
Schoetensack W, Bischler P, Dittmann ECH, Steinijans V (1977) Tierexperimentelle Untersuchungen über den Einfluß des Antihypertensivums Urapidil auf den Kreislauf und die Kreislaufregulation. Arzneimittel-Forschung/Drug Res 27:1908–1919
Schümann HJ, Bielefeld F-W (1986) The effect of urapidil on cardiac α- and β-adrenoceptors. Arzneimittel-Forschung/Drug Res 36:1471–1476
Van Zwieten PA, de Jonge A, Wilffert B, Timmermans PBMWM, Beckeringh JJ, Thoolen MJMC (1985) Cardiovascular effects and interaction with adrenoceptors of urapidil. Arch Int Pharmacodyn Ther 276:180–201
Author information
Authors and Affiliations
Additional information
Send offprint requests to G. Groß
Rights and permissions
About this article
Cite this article
Groß, G., Hanft, G. & Kolassa, N. Urapidil and some analogues with hypotensive properties show high affinities for 5-hydroxytryptamine (5-HT) binding sites of the 5-HT1A subtype and for α1-adrenoceptor binding sites. Naunyn-Schmiedeberg's Arch Pharmacol 336, 597–601 (1987). https://doi.org/10.1007/BF00165749
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00165749