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Bioorg Med Chem Lett. 2016 Nov 1;26(21):5315-5321. doi: 10.1016/j.bmcl.2016.09.037. Epub 2016 Sep 15.

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

Author information

1
Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland. Electronic address: awaszkie@cm-uj.krakow.pl.
2
Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
3
Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
4
Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.

Abstract

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-HT1A, 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 (Ki=23.5±1.3, α12=15.77, pKB=8.538±0.109). It was active in all tested doses in vivo (1, 0.5, and 0.1mg/kg) and it reduced blood pressure by 10-13% at the dose of 1mg/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 5mg/kgb.w. (mice, i.p.) without influence on spontaneous activity (mice, i.p.).

KEYWORDS:

5-HT; Adrenergic receptors; Hypertension; Hypotensive; Phenylpiperazine; Synthesis; α(1)-Antagonist

PMID:
27692547
DOI:
10.1016/j.bmcl.2016.09.037
[Indexed for MEDLINE]

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