Abstract
The Ca 2+-antagonistic properties of elnadipine 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 K i-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 IC 50 values only amounts to 9 (5 × 10 −7 to 4.5 × 10 −6 M). In contrast to Ca 2+-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 Ca 2+-antagonistic potency. The following conclusions regarding structural determinants of Ca 2+- 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 Ca 2+-antagonistic potency; correspondingly the unsubstituted compound is the strongest Ca 2+- and the weakest CaM-antagonist; 1,3,4-oxadiazole substitution is superior to 1,2,4-oxadiazole as regards Ca 2+- and CaM-antagonistic potency.
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