title: 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.
abstract: Four series of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-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]triazolo[3,4-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.
authors.affiliation: Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, Yanbian University College of Pharmacy, Yanji 133000, PR China.
authors.forename: Long-Xu
authors.initials: LX
authors.lastname: Ma
authors.affiliation: Department of Orthopedics, Yanbian University Affiliated Hospital, 133000, PR China.
authors.forename: Bai-Ri
authors.initials: BR
authors.lastname: Cui
authors.affiliation: Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, Yanbian University College of Pharmacy, Yanji 133000, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, Yanbian University College of Pharmacy, Yanji 133000, PR China.
authors.forename: Jia-Chun
authors.initials: JC
authors.lastname: Liu
authors.affiliation: Yanbian University College of Medicine, Yanji 133000, PR China.
authors.forename: Xun
authors.initials: X
authors.lastname: Cui
authors.affiliation: Yanbian University College of Medicine, Yanji 133000, PR China. Electronic address: liuliping@ybu.edu.cn.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Liu
authors.affiliation: Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, Yanbian University College of Pharmacy, Yanji 133000, PR China. Electronic address: piaohuri@yahoo.com.cn.
authors.forename: Hu-Ri
authors.initials: HR
authors.lastname: Piao
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D011817:Rabbits; D013318:Stroke Volume / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: C000596313:(4-((1,2,4)triazolo(3,4-a)phthalazin-6-yl)piperazin-1-yl)(p-tolyl)methanone; D010793:Phthalazines; D010879:Piperazines; D014230:Triazoles; D000077489:Piperazine; C037012:tetrazolo(5,1-a)phthalazine
keywords: Cinnamylpiperazine; Positive inotropic activity; Stroke volume; Tetrazolo[5,1-a]phthalazine; [1,2,4]Triazolo[3,4-a]phthalazine