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

Abstract

Three isoeugenol-based eugenosedin chlorphenylpiperazine derivatives, Eu-A, Eu-B, and Eu-C, were synthesized and tested for their serotonergic, adrenergic antagonist, antioxidant, and antiaggregation activities. In radioligand binding assays, all three agents displayed significant binding affinities on a 1 , a 2 , b 1 , 5-HT 1B , and 5-HT 2A receptors. In human platelet, they inhibited epinephrine and 5-HTinduced aggregation, and in human platelet with a 2 and 5-HT 2A 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 mmol) 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 mM) competitively antagonized norepinephrine-, clonidine-, and 5-HT (10 À8 -10 À4 M)-induced vasocontraction in isolated rat aorta, and competitively antagonized isoproterenol (10 À8 -10 À4 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 1 , all three agents antagonized 5-nonyloxytryptamine-and 5-HT-induced vasocontractions. These findings show that Eu-A, Eu-B, and Eu-C possess functional a 1 , a 2 , b 1 , 5-HT 1B , and 5-HT 2A receptor blocking activities. In conclusion, the changes in the position of chloride at phenylpiperazine influenced the serotonergic receptor, adrenoceptor DDR Published online in Wiley InterScience (www.interscience.wiley. com).

Eugenosedin-A prevents high-fat diet increased adhesion molecules through inhibition of MAPK- and p65-mediated NF-κB pathway in rat model

“…had shown to inhibit the NF‐κB pathway beneficial to the amelioration of hyperlipidaemia‐induced adhesion molecules. We have shown that eugenosedin‐A, a 5‐HT 1B/2A and α 1 /α 2 /β 1 ‐adrenergic blocker, is capable of reducing inflammation, scavenging free radicals and inhibiting platelet aggregation . Eugenosedin‐A also reduces obesity‐related hyperglycaemia, hyperinsulinaemia, hyperlipidaemia and MAPKs‐ and p65‐mediated NF‐κB‐induced inflammation .…”