ETRAHYDRO-3,6-METHANO-1,5-BENZODIAZOCINE-2,4-DIONE (BA-41899) - REPRESENTATIVE OF A NOVEL CLASS OF PURELY CALCIUM-SENSITIZING AGENTS

BA 41899 trahydro-3,6-methano-1,5-benzodiazocine-2,4-dione, 6) is a st ructurally novel 1,5-benzodiazocine derivative and represents the prot otype of a hitherto unknown class of positive inotropic Ca2+-sensitizi ng agents. It is completely devoid of phosphodiesterase (PDE) III inhi bitory activity or any other known inotropic mechanism. BA 41899 (6) e xhibits a pharmacological in vitro profile comprising Ca2+-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 positi ve inotropic effect. Conversely, the negative chronotropic action resi des in the corresponding (-)-enantiomer, CGP 48508 ((-)-6). Ah the eff ects are exerted in the low micromolar range. The positive inotropic a ction of CGP 48506 ((+)-6) is associated with a decelerating effect on contraction and, more prominently, relaxation dynamics in isolated gu inea pig atria. In contrast to Ca2+-sensitizing PDE inhibitors, CGP 48 506 ((+)-6) does not increase maximum Ca2+-activated force in myocardi al skinned fibers.