title: New arylsparteine derivatives as positive inotropic drugs.
abstract: Positive inotropic agents are fundamental in the treatment of heart failure; however, their arrhythmogenic liability and the increased myocardial oxygen demand strongly limit their therapeutic utility. Pursuing our study on cardiovascular activities of lupin alkaloid derivatives, several 2-(4-substituted-phenyl)-2-dehydrosparteines and 2-(4-substituted-phenyl)sparteines were prepared and tested for inotropic and chronotropic activities on isolated guinea pig atria. Four compounds (6b, 6e, 7b, and 7f) exhibited significant inotropism that, at the higher concentrations, was followed by negative inotropism or toxicity. Compound 7e (2-(4-tolyl)sparteine) exhibited a steep dose-depending inotropic activity up to the highest concentration tested (300 µM) with an Emaxof 116.5 ± 3.4% of basal force, proving less potent but much more active in comparison to the highest concentrations tested of digoxin and milrinone having Emaxof 87.5 ± 3.1% and 52.2 ± 1.1%, respectively. Finally, docking studies suggested that the relevant sparteine derivatives could target the sigma-1 receptor, whose involvement in cardiac activity is well documented.
authors.affiliation: a Department of Pharmacy , University of Genoa , Genoa , Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Boido
authors.affiliation: a Department of Pharmacy , University of Genoa , Genoa , Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Ercoli
authors.affiliation: a Department of Pharmacy , University of Genoa , Genoa , Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Tonelli
authors.affiliation: a Department of Pharmacy , University of Genoa , Genoa , Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Novelli
authors.affiliation: a Department of Pharmacy , University of Genoa , Genoa , Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Tasso
authors.affiliation: a Department of Pharmacy , University of Genoa , Genoa , Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sparatore
authors.affiliation: a Department of Pharmacy , University of Genoa , Genoa , Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cichero
authors.affiliation: a Department of Pharmacy , University of Genoa , Genoa , Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.affiliation: b Department of Pharmaceutical and Pharmacological Sciences , University of Padova , Padova , Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Dorigo
authors.affiliation: b Department of Pharmaceutical and Pharmacological Sciences , University of Padova , Padova , Italy.
authors.forename: Guglielmina
authors.initials: G
authors.lastname: Froldi
mesh_terms: D000818:Animals; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002316:Cardiotonic Agents / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats; D013034:Sparteine / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D013034:Sparteine
keywords: 2-aryl-2-dehydrosparteines; 2-arylsparteines; Lupin alkaloids; positive inotropic agents