Novel hypotensive agents from Verbesina caracasana. 6. Synthesis and pharmacology of caracasandiamide.
Caracasandiamide, a second hypotensive agent isolated from Verbesina caracasana, 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, 415-418). The structure was confirmed by synthesis starting from beta-truxinic acid obtained by photoaddition of 3, 4-dimethoxycinnamic acid. The dimer was coupled with 2 mol of prenylagmatine to give caracasandiamide in satisfactory yield. By contrast, the direct photodimerization of caracasanamide was unsuccessful. Caracasandiamide, assayed by the iv route in anesthetized rats at doses ranging from 50 to 3200 microgram/kg of body weight, was found to have no appreciable effect on heart rate. At lower doses, the drug stimulates breathing and increases cardiac inotropism, stroke volume, and cardiac output, thus augmenting blood pressure and aortic flow. At higher doses, caracasandiamide depresses breathing likely through central neurogenic mechanisms (not involved in the cardiovascular effects), continues to stimulate cardiac 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-dependent as well as M(2)- and M(4)-cholinergic receptor-dependent transductional pathways both in cardiovascular myocells and at the level of the postganglionic sympathetic endings (with reserpine- and guanethidine-like mechanisms). The cardiovascular effects of caracasandiamide, different from those of caracasanamide, do not depend on significant actions on the central nervous system and on baroreflex pathways. In a similar manner and more effective than caracasanamide, caracasandiamide may be considered a hypotensive and 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.
Carmignani
M
M
Dipartimento di Biologia di Base e Applicata, Sezione di Farmacologia, Università di L'Aquila, 67010 Coppito (AQ), Italy.
Volpe
A R
AR
Delle Monache
F
F
Botta
B
B
Espinal
R
R
De Bonnevaux
S C
SC
De Luca
C
C
Botta
M
M
Corelli
F
F
Tafi
A
A
Ripanti
G
G
Monache
G D
GD
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003503:Cyclobutanes / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006868:Hydrolysis; D007275:Injections, Intravenous; D008297:Male; D010936:Plant Extracts / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D015656:Respiratory Mechanics / Q000187:drug effects; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013318:Stroke Volume / Q000187:drug effects; D013990:Tidal Volume; D017725:Ventricular Pressure / Q000187:drug effects
D000959:Antihypertensive Agents; D003503:Cyclobutanes; D006146:Guanidines; D010936:Plant Extracts; C120838:caracasandiamide