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.
Herold
P
P
Cardiovascular Research Department, Ciba-Geigy Limited, Basel, Switzerland.
Herzig
J W
JW
Wenk
P
P
Leutert
T
T
Zbinden
P
P
Fuhrer
W
W
Stutz
S
S
Schenker
K
K
Meier
M
M
Rihs
G
G
D000818:Animals; D001392:Azocines / Q000138:chemical synthesis* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D004558:Electric Stimulation; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D013552:Swine
D001392:Azocines; D002316:Cardiotonic Agents; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; C095056:BA 41899; D002118:Calcium