Novel hypotensive agents from Verbesina caracasana. 6. Synthesis and pharmacology of caracasandiamide

Caracasancliamide, a second hypotensive agent isolated from Verbesina carac asana, is the cyclobutane dimer (truxinic type) of the previously reported 1-[(3,4-dimethoxycinnamoyl)amino]-4-[(3-methyl-2-butenyl)guanidino]butane ( caracasanamide) (Delle Monache, G.; et al. BioMed. Chem. Lett. 1992, 25, 41 5-418). The structure was confirmed by synthesis starting from beta-truxini c acid obtained by photoaddition of 3,4-dimethoxycinnamic acid. The dimer w as coupled with 2 mol of prenylagmatine to give caracasandiamide in satisfa ctory yield. By contrast, the direct photodimerization of caracasanamide wa s unsuccessful. Caracasandiamide, assayed by the iv route in anesthetized r ats at doses ranging from 50 to 3200 mu g/kg of body weight, was found to h ave! no appreciable effect on heart rate. At lower doses, the drug stimulat es breathing and increases cardiac inotropism, stroke volume, and cardiac o utput, thus augmenting blood pressure and aortic flow. At higher doses, car acasandiamide depresses breathing likely through central neurogenic mechani sms (not involved in the cardiovascular effects), continues to stimulate ca rdiac inotropism, and induces, by reducing peripheral vascular resistance, arterial hypotension with reduction of both aortic flow and stroke volume. These cardiovascular effects appear to involve complex interactions at the level of the peripheral beta(1)-, beta(2)-, and alpha(2)-adrenoreceptor-dep endent as well as M-2- and M-4-cholinergic receptor-dependent transductiona l pathways both in cardiovascular myocells and at the level of the postgang lionic sympathetic endings (with reserpine- and guanethidine-like mechanism s). The cardiovascular effects of caracasandiamide, different from those of caracasanamide, do not depend, on significant actions on the central nervo us system and on baroreflex path-ways. In a similar manner and more effecti ve than caracasanamide, caracasandiamide may be considered a hypotensive an d antihypertensive drug. It is devoid of some of the negative side effects, e.g., reflex tachycardia and decreased cardiac inotropism, which are shown by the majority of the most common antihypertensive and vasodilator drugs.