Novel hypotensive agents from Verbesina caracasana. 8. Synthesis and pharmacology of (3,4-dimethoxycinnamoyl)-N1-agmatine and synthetic analogues

The more polar metabolites from the Venezuelan plant Verbesina caracasana, i.e., N3-prenylagmatine, (3,4-dimethoxycinnamoyl)-N1-agmatine, agmatine, and galegine (prenylguanidine), previously reported (Delle Monache, G.; et al. BioMed. Chem. Lett. 1999, 9, 3249-3254), have been synthesized following a biosynthetic strategy. The pharmacol. profiles of various synthetic analogs of (3,4-dimethoxycinnamoyl)-N1-agmatine (G5) were also analyzed, to shed some light on the structure-activity relationship of these compds. Derivs. with the (E)-configuration and/or with a p-methoxybenzoyl moiety were found to be responsible for higher hypotensive effects, which were assocd. with a slight and, in some cases, not dose-related increase of cardiac inotropism, with variable and not significant chronotropic responses, and, only at higher doses, with effects of respiratory depression. Either an increase (to six) or a decrease (to two) of the no. of methylene groups in the alkyl chain of (E)-G5 did not change blood pressure responses, while slightly increasing the pos. inotropic ones. At pharmacol. doses, all the studied compds. showed hypotensive and slight pos. inotropic effects without relevant chronotropic and respiratory actions.