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

• The series of pyrrolidin-2-one derivatives were synthesized.
• The compounds obtained were evaluated for their affinity for α1- and α2-adrenoceptors.
• Compound with pKi (α1) ⩾6.44 were evaluated in functional bioassays for intrinsic activity at α1A- and α1B-adrenoceptors.
• Selected compounds were subjected to preliminary in vivo studies.

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 α1- and α2-adrenoceptors were assessed. The compound with highest affinity for the α1-adrenoceptors was 1-{4-[4-(2-chloro-phenyl)-piperazin-1-yl]-butyl}-pyrrolidin-2-one (10h) with pKi = 7.30. Compound with pKi (α1) ⩾6.44 were evaluated in functional bioassays for intrinsic activity at α1A- and α1B-adrenoceptors. All compounds tested were antagonists of the α1B-adrenoceptors. Additionally, compounds 10e and 10h were α1A-adrenoceptors antagonist. The dual α1A-/α1B-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.

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