Calmodulin and troponin C as targets for drug action.
In this study, ligands from various chemical classes were investigated with respect to their relative affinities to calmodulin (CaM) and troponin C (TnC), using the fluorescent dye 3,3'-dipropylthiocarbocyanine iodide (diS-C3-5'). In parallel, functional tests were carried out determining the effects of the ligands on the CaM activated cyclic nucleotide phosphodiesterase (PDE) activity and the TnC mediated Ca-sensitivity of skinned myocardial fibres and cardiac myofibrils. The following results were obtained: 1) As a rule, most of the ligands tested had higher affinities to CaM than to TnC. 2) Even within one and the same pharmacological class (e.g. phenothiazines) the relative affinities for CaM and TnC varied considerably, trifluoperazine (TFP) or levomepromazine (LMP) showing low or no CaM specificity, methophenazine (MP) on the other hand being highly selective for CaM by a factor of more than 200. 3) In all cases tested, the functional tests were in good quantitative agreement with the binding data, showing inhibition of CaM stimulated PDE activity and Ca-sensitizing effects in concentrations corresponding well with the respective drug affinities to CaM and TnC, respectively. 4) It is concluded that a) interaction of ligands with TnC can lead to Ca-sensitization of the cardiac contractile system and a positive inotropic effect without a concomitant elevation of the intracellular level of activator Ca. This may result in a novel cardiotonic principle avoiding the common side effects of 'classical' positive inotropic agents due to Ca-overload. b) drug selectivity for TnC or CaM appears chemically achievable.
D000818:Animals; D001570:Benzodiazepinones / Q000493:pharmacokinetics / Q000494:pharmacology; D002069:Butaclamol / Q000493:pharmacokinetics / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism*; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism; D010640:Phenothiazines / Q000493:pharmacokinetics / Q000494:pharmacology; D013552:Swine; D014336:Troponin / Q000378:metabolism*; D019209:Troponin C
D001570:Benzodiazepinones; D002147:Calmodulin; D010640:Phenothiazines; D014336:Troponin; D019209:Troponin C; C028513:4'-chlorodiazepam; D002069:Butaclamol; D002118:Calcium