Synthesis and positive inotropic evaluation of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine derivatives bearing substituted piperazine moieties |
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| Institution: | 1. University of Oregon, Oregon Institute of Marine Biology, PO Box 5389, Charleston, OR 97420, United States;2. University of California Santa Barbara, Bren School of Environmental Science & Management, 2400 Bren Hall, Santa Barbara, CA 93106-5131, United States;3. University of California Davis, Department of Environmental Science and Policy, Bodega Marine Laboratory, PO Box 247, Bodega Bay, CA 94923, United States |
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| Abstract: | Four series of 1,2,4]triazolo3,4-a]phthalazine and tetrazolo5,1-a]phthalazine derivatives bearing substituted piperazine moieties were synthesized and evaluated for their positive inotropic activity by measuring the left atrium stroke volume in isolated rabbit-heart preparations. Several compounds were developed and showed favorable activities compared to the standard drug milrinone, with (4-(1,2,4]triazolo3,4-a]phthalazin-6-yl)piperazin-1-yl)(p-tolyl)methanone (5g) being identified as the most potent with an increased stroke volume of 19.15 ± 0.22% (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10–5 M. A preliminary study of mechanism of action revealed that 5g displayed its positive inotropic effect may be related to the PDE-cAMP-PKA signaling pathway. Compounds exhibiting inotropic effects were also evaluated in terms of the chronotropic effects. |
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| Keywords: | Cinnamylpiperazine Positive inotropic activity Stroke volume |
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