Synthesis and activity of newly designed aroxyalkyl or aroxyethoxyethyl derivatives of piperazine on the cardiovascular and the central nervous systems.
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, α2and 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 α1receptor antagonist (Ki=23.5±1.3, α1/α2=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.).
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.
Anna Maria
AM
Waszkielewicz
Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
Monika
M
Kubacka
Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
Katarzyna
K
Pańczyk
Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
Szczepan
S
Mogilski
Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
Agata
A
Siwek
Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
Monika
M
Głuch-Lutwin
Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
Anna
A
Gryboś
Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
Barbara
B
Filipek
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000138:chemical synthesis / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002319:Cardiovascular System / Q000187:drug effects*; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000187:drug effects*; D006801:Humans; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats
D018687:Antidepressive Agents, Second-Generation; D000959:Antihypertensive Agents; D010879:Piperazines
5-HT; Adrenergic receptors; Hypertension; Hypotensive; Phenylpiperazine; Synthesis; α(1)-Antagonist