Novel histaprodifen analogues as potent histamine H1-receptor agonists in the pithed and in the anaesthetized rat

被引：0

作者：

Schlicker E. ^{[1
]}

Kozlowska H. ^{[2
]}

Kwolek G. ^{[2
]}

Malinowska B. ^{[2
]}

Kramer K. ^{[3
]}

Pertz H.H. ^{[3
]}

Elz S. ^{[3
]}

Schunack W. ^{[3
]}

机构：

[1] Institut für Pharmakologie/Toxikologie, Universität Bonn, 53113 Bonn

[2] Zakład Fizjologii Doświadczalnej, 15-230 Białystok, Akademia Medyczna

[3] Institut für Pharmazie, Freie Universität Berlin, 14195 Berlin

来源：

Naunyn-Schmiedeberg's Archives of Pharmacology | 2001年 / 364卷 / 1期

关键词：

Anaesthetized rats; Cardiovascular system; Dimetindene; H[!sub]1[!/sub]-receptor agonists; Methylhistaprodifen; Pithed rats;

D O I：

10.1007/s002100100414

中图分类号：

学科分类号：

摘要：

We have shown previously that histaprodifen and its Nα-substituted analogues methylhistaprodifen and dimethylhistaprodifen are highly potent H1-receptor agonists in vivo. The aim of the present study was to examine the influence of four newly synthesized histaprodifen analogues, 3-fluoro-methylhistaprodifen (1), Nα-imidazolyl-ethylhistaprodifen (2), bis-histaprodifen (3) and Nα-methyl-bis-histaprodifen (4), on the cardiovascular system in the pithed and in the anaesthetized rat. In pithed and vagotomized rats, diastolic blood pressure (which was increased to 80-85 mmHg by vasopressin infusion) was decreased dose dependently by methylhistaprodifen (the reference compound) and by compounds 1-4. The maximum decrease was about 47-50 mmHg for methylhistaprodifen and compounds 1, 2 and 3. Their potencies, expressed as pED50 (the negative logarithm of the dose in mole per kilogram body weight that decreased diastolic blood pressure by 25 mmHg), were 8.31, 8.23, 8.26 and 7.84, respectively. With compound 4 the maximal effect was not achieved at doses up to 1 μmol/kg (the latter dose decreased blood pressure by about 30 mmHg; pED50≈6.5). The vasodepressor effect of the five compounds was attenuated by the H1-receptor antagonist dimetindene (1 μmol/kg) but was not changed by combined administration of the H2- and H3-receptor antagonists ranitidine and thioperamide (1 μmol/kg each), by combined administration of the α1- and α2-adrenoceptor antagonists prazosin and rauwolscine (1 μmol/kg each) or by the β-adrenoceptor antagonist propranolol (3 μmol/kg). In anaesthetized rats methylhistaprodifen and compounds 1-4 induced almost the same fall in blood pressure as in pithed and vagotomized animals; the effects were sensitive to blockade by dimetindene (1 μmol/kg). Higher doses of compounds 1 and 2 (1 μmol/kg) increased heart rate in pithed and vagotomized rats in a manner sensitive to propranolol (3 μmol/kg) but insensitive to dimetindene (3 μmol/kg). The same dose of methylhistaprodifen and of compounds 3 and 4 failed to affect heart rate. We conclude that the agonistic potency of compounds 1 and 2 at H1-receptors in the cardiovascular system of the rat equals that of methylhistaprodifen, the most potent histamine H1-receptor agonist available until recently. Compounds 1 and 2 exhibit sympathomimetic activity at high doses.

引用

页码：14 / 20

页数：6

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