Synthesis and activity of newly designed aroxyalkyl or aroxyethoxyethyl derivatives of piperazine on the cardiovascular and the central nervous systems

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• 作者：Anna Maria Waszkielewicz^a ; ^{awaszkie@cm-uj.krakow.pl" class="auth_mail" title="E-mail the corresponding author} ; Monika Kubacka^b ; Katarzyna Pańczyk^a ; Szczepan Mogilski^b ; Agata Siwek^c ; Monika Głuch-Lutwin^c ; Anna Gryboś^c ; Barbara Filipek^b
• 关键词：5-HT ; α1-Antagonist ; Adrenergic receptors ; Hypertension ; Hypotensive ; Phenylpiperazine ; Synthesis
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：26
• 期：21
• 页码：5315-5321
• 全文大小：989 K

文摘

In the search for new hypotensive agents some new aroxyalkyl or aroxyethoxyethyl derivatives of piperazine have been synthesized and evaluated for their pharmacological properties. Pharmacological tests included receptor binding assays toward adrenergic receptors α₁, α₂ and β₁, additionally 5-HT_1A, functional bioassay and in vivo evaluation of hypotensive activity as well as antidepressant-like potential. All the tested compounds exhibited α₁-antagonistic properties, three of them possessed also hypotensive activity in rats. The most promising compound 3 1-[4-(2,6-dimethylphenoxy)butyl]-4-(2-methoxyphenyl)piperazine hydrochloride was a selective α₁ receptor antagonist (K_i = 23.5 ± 1.3, α₁/α₂ = 15.77, pK_B = 8.538 ± 0.109). It was active in all tested doses in vivo (1, 0.5, and 0.1 mg/kg) and it reduced blood pressure by 10–13% at the dose of 1 mg/kg (rats, i.v.). Compound 5 1-[2-(2,3-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine dihydrochloride exhibited the lowest dose for antidepressant-like activity 5 mg/kg b.w. (mice, i.p.) without influence on spontaneous activity (mice, i.p.).