NEW CALMODULIN ANTAGONISTS OF THE DIPHENYLALKYLAMINE TYPE .1. BIOLOGICAL-ACTIVITY, SAR AND THE ROLE OF LIPOPHILICITY

Potency and selectivity of currently available calmodulin (CaM) antago nists is rather limited. We attempted to improve the CaM-antagonistic activity in a new series of analogues of the CaM-antagonist prenylamin e. The biological test system used was the CaM-stimulated phosphodiest erase. Insertion of a double bond or heteroatoms (O, S) at the ring co nnecting carbon in the benzhydryl part of the molecule increases poten cy in comparison to the lead compound prenylamine. Chain length is opt imal with 4 atoms-nitrogen-3 atoms. Regarding benzhydryl substitution, halogenation results in a significantly increased improvement of CaM- inhibitory potency than methylation; parasubstitution is superior to o rtho-substitution. Secondary nitrogen seems to be advantageous as comp ared to tertiary amine. Lipophilicity has been detected as a prime phy sico-chemical descriptor of CaM-antagonistic potency. The role of lipo philicity, however, differs in a quantitative sense when the subgroups are considered. It decreases within the subgroups in the following ma nner: saturated alkyl chain- > double bond- > sulphur- > oxygen-deriva tives. Amongst the compounds described, new CaM-antagonists with remar kably high potency have been detected.