Histaprodifen, methylhistaprodifen, and dimethylhistaprodifen are potent H1-receptor agonists in the pithed and in the anaesthetized rat

Abstract

Selective H₂- and H₃-receptor agonists, exhibiting an at least tenfold higher potency than histamine itself at the respective receptors, have been known for several years. Selective H₁-receptor agonists with a potency exceeding that of histamine have become available only recently; the most potent are methylhistaprodifen and dimethylhistaprodifen [N ^α-methyl- and N ^α,N ^α-dimethyl-2-(3,3-diphenylpropyl)histamine, respectively] with 3.4- and 2.4-fold higher potencies than histamine in vitro (in the guinea-pig ileum). The aim of the present study was to examine whether these compounds and the parent compound histaprodifen are potent H₁-receptor agonists in the pithed and in the anaesthetized rat. In pithed, vagotomized rats diastolic blood pressure was decreased by 2-(2-thiazolyl)ethanamine i.v. (which was used as a reference H₁-receptor agonist) and by histaprodifen, methylhistaprodifen, and dimethylhistaprodifen; the maximum decrease was about 45 mmHg for each compound, and the potencies, expressed as pED₅₀, the negative logarithm of the dose (in mole per kilogram body weight) eliciting a half-maximal response, were 7.23, 7.55, 8.43 and 8.12, respectively. The dose/response curves of the four compounds were shifted to the right to about the same extent by the H₁-receptor antagonist dimetindene (1 µmol/kg i.v.). The vasodepressor response was not affected by combined i.v. administration of the H₂- and H₃-receptor antagonists ranitidine and thioperamide, by combined i.v. administration of the α₁- and α₂-adrenoceptor antagonists prazosin and rauwolscine, and by the β-adrenoceptor antagonist propranolol i.v. but was attenuated by the inhibitor of NO synthase, N ^ω-nitro-l-arginine methyl ester i.v. In anaesthetized rats 2-(2-thiazolyl)ethanamine, histaprodifen, methylhistaprodifen and dimethylhistaprodifen i.v. also decreased diastolic blood pressure in a manner sensitive to dimetindene i.v. Our data show that histaprodifen and, in particular, methyl- and dimethylhistaprodifen are highly potent H₁-receptor agonists in vivo.