CALCIUM-ENTRY BLOCKERS AND ACTIVATORS - CONFORMATIONAL AND STRUCTURALDETERMINANTS OF DIHYDROPYRIMIDINE CALCIUM-CHANNEL MODULATORS

Dihydropyrimidines 4, 6, and 15, uniquely designed to unambiguously es tablish structural and conformational determinants for DHP receptor oc cupation and for modulation of calcium channel function, were prepared and examined for calcium channel modulation. Our results confirm and firmly establish a preference for syn-orientation of an unsymmetricall y substituted aryl moiety at the DHP receptor (15d vs 15e). We propose a normal vs capsized DHP boat model to explain structural and conform ational requirements for modulation of calcium channel function that r equires an obligatory left-hand side alkoxy cis-carbonyl interaction f or maximal DHP receptor affinity, the effect on channel function being determined by orientation of the 4-aryl group. Enantiomers having an up-oriented pseudoaxial aryl group (normal DHP boat) will elicit calci um antagonist activity, whereas enantiomers having a down-oriented pse udoaxial aryl group (capsized DHP boat) will elicit calcium agonist ac tivity. Single enantiomers of macrocyclic lactone 15b demonstrate oppo site channel activity. Antagonist activity resides in enantiomer 15b-A (S-configuration, left-hand side alkoxy cis-carbonyl with up-oriented pseudoaxial aryl group and normal DHP boat), whereas agonist activity resides in enantiomer 15b-B (R-configuration, left-hand side alkoxy c is-carbonyl with down-oriented pseudoaxial aryl group and capsized DHP boat). Moreover, this model is consistent with and provides a rationa l explanation of previous literature in this area, most notably the ob servation of chiral inversion and potency diminution upon replacement of ester by hydrogen in the Bay K 8644 series.