[Structural congeners of guanfu base A and their antiarrhythmic activity]

Guanfu base A (GFA) is an alkaloid isolated from the root of Aconitum coreanum and is effective in several experimental arrhythmia models. GFA can effectively antagonize aconitine-induced arrhythmia, significantly reduce CaCl2-induced incidence of ventricular fibrillation in rats and markedly raise the ventricular fibrillation threshold to electrical stimulation in rabbits and cats. It would be valuable in clinic to treat ventricular fibrillation. Thus, we chose GFA as lead compound for chemical modification. From the view point of stereochemistry, GFA is a rigid structure and can be considered as composed of two layers. The first layer is a hydrogenated phenanthrene ring; the second is the alkylamino chain containing hydroxy and acetoxy groups [formula: see text]. It was speculated that the skeleton of such chain might play as pharmacophore contributing to the biological activity. In order to reduce the size of the molecule and simplify the chemical structure of GFA, the hydrogenated phenanthrene was removed and an aryl residue commonly occurred in the structure of antiarrhythmic agents was introduced. Thus, fourteen derivatives of phenylpropanediolamine were designed and synthesized. There is a hydrogenated indolizine ring in the structure of GFA and a indolizine ring in the structure of class III antiarrhythmic agent--butoprizine. By combing the structural feature of GFA with that of butoprizine, nine indolizine derivatives were also designed and synthesized. Screening test of 23 compounds indicated that phenylpropanediolamine derivatives--I1, I2, I3, I7, I8, I14, and indolizine derivatives--II2 markedly antagonized chloroform-induced arrhythmias in rats. Among them I2, I3, I7 and I8, appeared to be more potent than GFA.