Effect of natural and synthetic benzyl benzoates on calmodulin.
The present investigation describes the effect of the spasmolytic benzylbenzoates 1-9 from Brickellia veronicifolia on CaM using a functional in vitro enzymatic assay. Bovine brain PDE1 was used as a monitoring enzyme. The most active natural inhibitors of the system CaM-PDE1 were benzyl benzoates 3-5, which inhibited the activity of PDE1 in a concentration-dependent manner. In addition, three series of analogs of compound 4, compounds 10a-32a, were prepared and assayed. The benzyl benzoates from the first series, namely 10a-24a, possess no substituents on ring B but different number and position of hydroxyl or methoxy groups in ring A. The second group (25-32a), on the other hand, possesses an A ring identical to that on compound 4, but different substituents in Ring B. The most active compounds were 14a, 15a and 30a. These compounds were two to six times more potent than chlorpromazine, a well known CaM inhibitor. Benzyl benzoates 14a and 15a have methoxyl groups at C-2/C-4 and C-3/C-4 in ring A, respectively; while 30a, in addition to the methoxyl groups at C-2/C-6 of ring A, hold a benzoyloxy moiety at C-3' of ring B. Kinetic studies revealed that compounds 3, 4, 14a, 15a and 30a behave as competitive CaM antagonists.
Rivero-Cruz
Blanca
B
Departamentos de Farmacia y Bioquímica, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
Rivero-Cruz
Isabel
I
Rodríguez-Sotres
Rogelio
R
Mata
Rachel
R
D000818:Animals; D019659:Asteraceae / Q000737:chemistry; D001565:Benzoates / Q000737:chemistry* / Q000302:isolation & purification; D002147:Calmodulin / Q000737:chemistry*; D002417:Cattle; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D007700:Kinetics; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000302:isolation & purification
D001565:Benzoates; D002147:Calmodulin; D010727:Phosphoric Diester Hydrolases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C006723:benzyl benzoate