title: Role of the carboxylic group in the antispasmodic and vasorelaxant action displayed by kaurenoic acid.
abstract: The present work describes the investigation of the role of the carboxylic group in the structure-activity relationship of the diterpene ent-kaur-16-en-19-oic acid (kaurenoic acid, KA) in inhibiting rat aorta contraction. For this purpose the methylation of the C-19 carboxyl group of KA was carried out. The effects of the obtained ent-methyl-kaur-16-en-19-oate (KAMe) were compared with those induced by KA. Vascular reactivity experiments showed that KA (50 and 100 microM) concentration-dependently inhibited KCl-induced contraction in both endothelium-intact and denuded rat aortic rings. On the other hand, KAMe attenuated KCl-induced contraction at 100 microM, but not at 50 microM. KA also reduced CaCl(2)-induced contraction in Ca(2+)-free solution containing KCl (30 mM). Again, KAMe produced a less accentuated reduction in CaCl(2)-induced contraction than that induced by the acid KA. KAMe (1-450 microM) concentration-dependently relaxed KCl-pre-contracted rings (percentages of relaxation 82.57 +/- 1.65 and 70.55 +/- 4.71, respectively) with denuded endothelium. Similarly, the relaxation induced by KA on phenylephrine (Phe)-pre-contracted rings (73.06 +/- 3.68%) was more pronounced than that found for KAMe (53.68 +/- 4.75%). Pre-incubation of denuded rings for different periods with KA and KAMe showed that the equilibrium periods required by each compound to achieve its maximal inhibitory response on KCl-induced contraction are different. Collectively, our results provide functional evidence that methylation of the C-19 carboxyl group of KA reduces but does not abolish the antispasmodic activity displayed by KA. Additionally, we showed that the equilibrium period is a critical step for the inhibitory effect displayed by kaurane-type diterpenes.
authors.affiliation: Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Sergio R
authors.initials: SR
authors.lastname: Ambrosio
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Tirapelli
authors.forename: Silvia T
authors.initials: ST
authors.lastname: Coutinho
authors.forename: Dionéia C R
authors.initials: DC
authors.lastname: de Oliveira
authors.forename: Ana M
authors.initials: AM
authors.lastname: de Oliveira
authors.forename: Fernando B
authors.initials: FB
authors.lastname: Da Costa
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology; D003329:Coronary Vasospasm; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008745:Methylation; D009200:Myocardial Contraction / Q000187:drug effects*; D010936:Plant Extracts; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014664:Vasodilation
chemical_list: D002264:Carboxylic Acids; D004224:Diterpenes; D010936:Plant Extracts; C051436:kaurenoic acid