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 analogues of (3,4-dimethoxycinnamoyl)-N(1)-agmatine (G5) were also analyzed, to shed some light on the structure-activity relationship of these compounds. Derivatives with the (E)-configuration and/or with a p-methoxybenzoyl moiety were found to be responsible for higher hypotensive effects, which were associated with a slight and, in some cases, not dose-related increase of cardiac inotropism, with variable and not significant chronotopic responses, and, only at higher doses, with effects of respiratory depression. Either an increase (to six) or a decrease (to two) of the number of methylene groups in the alkyl chain of (E)-G5 did not change blood pressure responses, while slightly increasing the positive inotropic ones. At pharmacological doses, all the studied compounds showed hypotensive and slight positive inotropic effects without relevant chronotropic and respiratory actions.
Carmignani
M
M
Dipartimento di Biologia di Base e Applicata, Sezione di Farmacologia, Università di L'Aquila, 67010 Coppito (AQ), Italy. g.dellemonache@uniserv.ccr.rm.cnr.it
Volpe
A R
AR
Botta
B
B
Espinal
R
R
De Bonnevaux
S C
SC
De Luca
C
C
Botta
M
M
Corelli
F
F
Tafi
A
A
Sacco
R
R
Delle Monache
G
G
D000376:Agmatine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D010946:Plants, Medicinal / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014687:Venezuela
C435193:(3,4-dimethoxycinnamoyl)-N(1)-agmatine; D000959:Antihypertensive Agents; D006146:Guanidines; D000376:Agmatine