Calcium- and calmodulin-antagonism of Elnadipine (cas 103946-15-2) derivatives: comparative SAR

Add time:07/20/2019    Source:sciencedirect.com

The Ca2+-antagonistic properties of Elnadipine (cas 103946-15-2) derivatives have been quantified by means of binding experiments in bovine cerebral cortex membranes using 3H-nitrendipine. Competition experiments have shown a 308-fold concentration range of Ki-values (2.9 × 10−10 to 8.9 × 10−8) for elnadipine derivatives and a eudismic ratio for elnadipine and its (+)-enantiomer of 448. Calmodulin (CaM)-antagonistic properties have been measured in the test system of CaM-stimulated phosphodiesterase. The concentration range of IC50 values only amounts to 9 (5 × 10−7 to 4.5 × 10−6 M). In contrast to Ca2+-antagonism, enantioselectivity of CaM-inhibition by elnadipine is negligible. CaM-antagonistic potency of elnadipine derivatives is diminished by a factor of 10 to 5000 as compared to their Ca2+-antagonistic potency. The following conclusions regarding structural determinants of Ca2+- and CaM-antagonistic properties can be made: lipophilic substituents of the oxadiazole in 5-position of the dihydropyridine (DHP) ring increase the CaM-antagonistic and decrease the Ca2+-antagonistic potency; correspondingly the unsubstituted compound is the strongest Ca2+- and the weakest CaM-antagonist; 1,3,4-oxadiazole substitution is superior to 1,2,4-oxadiazole as regards Ca2+- and CaM-antagonistic potency.

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