Structure–activity relationships of isoeugenol‐based chlorophenylpiperazine derivatives on serotonergic/adrenergic receptor, platelet aggregation, and lipid peroxidation

Abstract

AbstractThree isoeugenol‐based eugenosedin chlorphenylpiperazine derivatives, Eu‐A, Eu‐B, and Eu‐C, were synthesized and tested for their serotonergic, adrenergic antagonist, antioxidant, and anti‐aggregation activities. In radioligand binding assays, all three agents displayed significant binding affinities on α1, α2, β1, 5‐HT1B, and 5‐HT2A receptors. In human platelet, they inhibited epinephrine and 5‐HT‐induced aggregation, and in human platelet with α2 and 5‐HT2A receptors they had a competitive binding effect. Eu‐B and Eu‐C were more potent than Eu‐A. All compounds had antioxidant effects derived from aryloxypropanolamine. Eu‐ A, Eu‐B, or Eu‐C (1, 3, 5 mg/kg iv) given to normotensive Wistar rats produced a dose‐dependent decrease in mean arterial blood pressure and heart rate and when injected into the cisternum, Eu‐A, Eu‐B, or Eu‐C (0.3, 0.03 µmol) increased blood pressure within 15 min. Pretreatment with any of the three agents inhibited clonidine (38 pmol)‐induced hypotension. In vitro experiments, Eu‐A, Eu‐B, or Eu‐C (1, 10, and 100 µM) competitively antagonized norepinephrine‐, clonidine‐, and 5‐HT (10−8–10−4 M)‐induced vasocontraction in isolated rat aorta, and competitively antagonized isoproterenol (10−8–10−4 M)‐induced positive inotropic effects in a concentration‐dependent manner in the isolated rat left atrium. In isolated rabbit ear arteries sensitized with 16 mM K+, all three agents antagonized 5‐nonyloxytryptamine‐ and 5‐HT‐induced vasocontractions. These findings show that Eu‐A, Eu‐B, and Eu‐C possess functional α1, α2, β1, 5‐HT1B, and 5‐HT2A receptor blocking activities. In conclusion, the changes in the position of chloride at phenylpiperazine influenced the serotonergic receptor, adrenoceptor antagonistic activities, but not anti‐aggregation and antioxidant activities. Drug Dev Res 71:1–9, 2010. © 2010 Wiley‐Liss, Inc.