title: Scaffold evaluation of liguzinediol analogs as novel cardiotonic agents.
abstract: Liguzinediol (LZDO) could mediate the positive inotropic effects through sarcoplasmic reticulum Ca2+ ATPase-dependent mechanism without the risk of arrhythmia. However, the pharmacophore of LZDO contributed to the activities was not clear. The aim of this work was to explore the relationship between positive inotropic effect and scaffold of LZDO as well as to check whether the pharmacophore of LZDO on anti-heart failure activity was located at the pyrazine ring. A series of LZDO analogs (3a-b, 4a-b, 9-19) were designed and synthesised, and their activities were evaluated on isolated heart contractility by Langendorff perfusion. The results showed that the efficacy of LZDO was reduced when the hydroxyl, carboxyl or ester moieties at the side chain position of LZDO were induced, and the para-dihydroxy in LZDO was necessary for its activity. Thus, the pharmacophore of the positive inotropic effect might be located at the whole scaffold of LZDO, but not at the pyrazine ring. The finding may provide an important clue of the pharmacophore for the development of novel cardiotonic agents.
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: K
authors.initials: K
authors.lastname: Qin
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: K
authors.initials: K
authors.lastname: Wen
authors.affiliation: State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
authors.forename: C J
authors.initials: CJ
authors.lastname: Zhu
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: N G
authors.initials: NG
authors.lastname: Li
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: H M
authors.initials: HM
authors.lastname: Bian
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: H M
authors.initials: HM
authors.lastname: Wen
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: L
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis; D006321:Heart / Q000187:drug effects; D006900:Hydroxylation; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: C572935:2,5-dihydroxymethyl-3,6-dimethylpyrazine; D002316:Cardiotonic Agents; D004952:Esters; D007202:Indicators and Reagents; D011719:Pyrazines