Novel hypotensive agents from Verbesina caracasana. 6. Synthesis and pharmacology of caracasandiamide.
| Title: | Novel hypotensive agents from Verbesina caracasana. 6. Synthesis and pharmacology of caracasandiamide. |
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| Authors: | Carmignani M; Dipartimento di Biologia di Base e Applicata, Sezione di Farmacologia, Università di L'Aquila, 67010 Coppito (AQ), Italy.; Volpe AR; Delle Monache F; Botta B; Espinal R; De Bonnevaux SC; De Luca C; Botta M; Corelli F; Tafi A; Ripanti G; Monache GD |
| Source: | Journal of medicinal chemistry [J Med Chem] 1999 Aug 12; Vol. 42 (16), pp. 3116-25. |
| Publication Type: | Comparative Study; Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print Cited Medium: Print ISSN: 0022-2623 (Print) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Washington Dc : American Chemical Society; Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| MeSH Terms: | Antihypertensive Agents/*chemical synthesis ; Cyclobutanes/*chemical synthesis ; Guanidines/*chemical synthesis; Antihypertensive Agents/administration & dosage ; Antihypertensive Agents/chemistry ; Antihypertensive Agents/pharmacology ; Blood Pressure/drug effects ; Cyclobutanes/administration & dosage ; Cyclobutanes/chemistry ; Cyclobutanes/pharmacology ; Guanidines/administration & dosage ; Guanidines/chemistry ; Guanidines/pharmacology ; Heart Rate/drug effects ; Plant Extracts/chemistry ; Respiratory Mechanics/drug effects ; Stroke Volume/drug effects ; Ventricular Pressure/drug effects ; Animals ; Hydrolysis ; Injections, Intravenous ; Male ; Rats ; Rats, Wistar ; Spectrometry, Mass, Fast Atom Bombardment ; Tidal Volume |
| Abstract: | 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. |
| Substance Nomenclature: | 0 (Antihypertensive Agents); 0 (Cyclobutanes); 0 (Guanidines); 0 (Plant Extracts); 0 (caracasandiamide) |
| Entry Date(s): | Date Created: 19990817 Date Completed: 19990902 Latest Revision: 20061115 |
| Update Code: | 20260130 |
| DOI: | 10.1021/jm991004l |
| PMID: | 10447956 |
| Database: | MEDLINE |
Comparative Study; Journal Article; Research Support, Non-U.S. Gov't