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 E_max of 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 E_max of 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.

Keywords: 2-aryl-2-dehydrosparteines; 2-arylsparteines; Lupin alkaloids; positive inotropic agents.

Figure 1.

Lupin alkaloids and derivatives investigated as inotropic agents.

Figure 2.

Inotropic effects of digoxin, milrinone and compound 7e. *p < 0.05 compound 7e versus milrinone.

Scheme 1:

Reagents and conditions: (a) dry Et₂O; reflux, 2 h; (b) dil. HCl; (c) H₂/Pd-C, EtOH, r.t.; (d) NaBH₄, EtOH; reflux, 4 h. *(±)-lupanine, for the sake of simplicity, only one enantiomer is shown.

Figure 3.

Chronotropic effects of digoxin, milrinone and compound 7e. *p < 0.05 compound 7e versus milrinone.

Figure 4.

Inotropic cytisine derivatives.

Figure 5.

Some arylalkyl amines with high affinity for sigma-1 receptor.

Figure 6.

X-ray crystallographic data of the human sigma-1 receptor and of the ligand PD144418. The most important residues are labeled and colored in orange.

Figure 7.

Docking mode of 7b and of 7e within the X-ray crystallographic data of the human sigma-1 receptor and of the ligand PD144418 (C atom; brown). The most important residues are labeled.