5-Methyl-6-phenyl-1,3,5,6-tetrahydro-3,6-methano-1,5-benzodiazocine-2,4-dione (BA 41899): representative of a novel class of purely calcium-sensitizing agents

BA 41899 (5-methyl-6-phenyl-1,3,5,6-tetrahydro-3,6-methano-1,5- benzodiazocine-2,4-dione, 6) is a structurally novel 1,5-benzodiazocine derivative and represents the prototype of a hitherto unknown class of positive inotropic Ca(2+)-sensitizing agents. It is completely devoid of phosphodiesterase (PDE) III inhibitory activity or any other known inotropic mechanism. BA 41899 (6) exhibits a pharmacological in vitro profile comprising Ca(2+)-sensitizing, positive inotropic, and negative chronotropic effects. CGP 48506 ((+)-6), the (+)-enantiomer of BA 41899 (6), enantiospecifically carries Ca2+ sensitization by up to a full pCa unit and a corresponding positive inotropic effect. Conversely, the negative chronotropic action resides in the corresponding (-)-enantiomer, CGP 48508 ((-)-6). All the effects are exerted in the low micromolar range. The positive inotropic action of CGP 48506 ((+)-6) is associated with a decelerating effect on contraction and, more prominently, relaxation dynamics in isolated guinea pig atria. In contrast to Ca(2+)-sensitizing PDE inhibitors, CGP 48506 ((+)-6) does not increase maximum Ca(2+)-activated force in myocardial skinned fibers.