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[摘要]：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 alpha(l), alpha(2), beta(1), 5-HT1B, and 5-HT2A receptors. In human platelet, they inhibited epinephrine and 5-HT-induced aggregation, and in human platelet with a2 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 mu mol) 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 mu M) 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 alpha(1,) alpha(2), beta(1), 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 71:285-293, 2010. (C) 2010 Wiley-Liss, Inc. |
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