Novel hypotensive agents from Verbesina caracasana. 8. Synthesis and pharmacology of (3,4-dimethoxycinnamoyl)-N-1-agmatine and synthetic analogues

The more polar metabolites from the Venezuelan plant Verbesina caracasana, i.e., N-3-prenylagmatine, (3,4-dimethoxycinnamoyl)-N-1-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 pharmacologic profiles of various synthetic a nalogues of (3,4-dimethoxycinnamoyl)-N-1-agmatine (G5) were also analyzed, to shed some light on the structure-activity relationship of these compound s, Derivatives with the (E)-configuration and/or with a p-methoxybenzoyl mo iety were found to be responsible for higher hypotensive effects, which wer e associated with a slight and, in some cases, not dose-related increase of cardiac inotropism, with variable and not significant chronotopic response s, and, only at higher doses, with effects of respiratory depression. Eithe r an increase (to six) or a decrease (to two) of the number of methylene gr oups in the alkyl chain of (E)-G5 did not change blood pressure responses, while slightly increasing the positive inotropic ones. At pharmacological d oses, all the studied compounds showed hypotensive and slight positive inot ropic effects without relevant chronotropic and respiratory actions.