alpha-Adrenoceptor antagonistic and hypotensive properties of novel arylpiperazine derivatives of pyrrolidin-2-one

作者：Zareba Paula; Dudek Magdalena; Lustyk Klaudia; Siwek Agata; Starowicz Gabriela; Bednarski Marek; Nowinski Leszek; Razny Katarzyna; Sapa Jacek; Malawska Barbara; Kulig Katarzyna^*

来源：Bioorganic & Medicinal Chemistry, 2015, 23(9): 2104-2111.

DOI：10.1016/j.bmc.2015.03.009

• alpha-Adrenoceptors antagonists
• Hypotensive activity
• Pyrrolidin-2-one derivatives
• Long-chain arylpiperazines

This study focused on a series of pyrrolidin-2-one derivatives connected via two or four methylene units to arylpiperazine fragment. The compounds obtained for alpha(1)- and alpha(2)-adrenoceptors were assessed. The compound with highest affinity for the alpha(1)-adrenoceptors was 1-{4-[4-(2-chloro-phenyl)-piperazin-1-yl]-butyl}-pyrrolidin-2-one (10h) with pK(i) = 7.30. Compound with pK(i) (alpha(1)) >= 6.44 were evaluated in functional bioassays for intrinsic activity at alpha(1A)- and alpha(1B)-adrenoceptors. All compounds tested were antagonists of the alpha(1B)-adrenoceptors. Additionally, compounds 10e and 10h were alpha(1A)-adrenoceptors antagonist. The dual alpha(1A)-/alpha(1B)-adrenoceptors antagonists, compounds 10e and 10h were also tested in vivo for their hypotensive activity in rats. These compounds, when dosed of 1.0 mg/kg iv in normotensive, anesthetized rats, significantly decreased systolic and diastolic pressure and their hypotensive effects lasted for longer than one hour.

• 出版日期2015-5-1