The dihydropyridine derivative 202-791: interpretation of the effects of the racemate considering inverse agonistic enantiomers.
1. The influence of the enantiomers and the racemate of the dihydropyridine derivative 202-791 [isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-nitro-3- pyridinecarboxylate] on force of contraction and action potential was studied in guinea-pig isolated papillary muscles. The effects were investigated during regular stimulation (1 Hz) and after a period of rest (10 min). 2. The enantiomers of the dihydropyridine derivative 202-791 had opposite effects on the mechanical and bioelectrical parameters: the (+,S)-enantiomer enhanced contractility and prolonged action potential duration whereas the (-,R)-enantiomer reduced force and shortened action potential duration. Analogous to the effects during regular stimulation, the post-rest adaptation was modified adversely: in the presence of the (+,S)-enantiomer the pattern of adaptation was intensified while the (-,R)-enantiomer caused an attenuation. The term 'inverse agonism' seems more suitable than the commonly used comparison of agonist and antagonist, because each enantiomer possesses intrinsic activity, albeit in opposite directions. 3. The racemate of 202-791 acted like the (+,S)-enantiomer. In concentrations up to 1 microM, the racemate increased the force of contraction to the same extent as if the cardiodepressant (-,R)-enantiomer was not present. Only at the highest concentration (3 microM) did the counteracting effect of the (-,R)-enantiomer become evident. The racemate prolonged the action potential duration like the (+,S)-enantiomer although to a lesser extent. Moreover, the typical post-rest adaptation of contractile force and action potential duration was accentuated by the racemate as with the (+,S)-enantiomer. 4. The results demonstrate that in case of 202-791, the effects of the racemate do not reflect the opposite actions of the two enantiomers, but rather mimic that of the (+,S)-enantiomer. A prediction concerning the effects of the enantiomers which is based on findings obtained with the racemate is not possible.
Damarowsky
M
M
Department of Pharmacology, University of Kiel, F.R.G.
Lüllmann
H
H
Ravens
U
U
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D009539:Nicotinic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D010069:Oxadiazoles; D010210:Papillary Muscles / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism
D009539:Nicotinic Acids; D010069:Oxadiazoles; C049834:PN 202-791