title: Inhibition of human cardiac cyclic AMP-phosphodiesterases by R 80122, a new selective cyclic AMP-phosphodiesterase III inhibitor: a comparison with other cardiotonic compounds.
abstract: Four cyclic AMP (cAMP)-phosphodiesterases (PDE) belonging to families I, II, III and IV were identified in homogenates from human failing hearts. On fractionation of cardiac membranes, the cyclic GMP (cGMP)-inhibitable cAMP-PDE III copurified with the sarcoplasmic reticulum. cAMP-PDE activities were separated from the soluble fraction by DEAE-ion exchange chromatography and identified as belonging to the four different families of cAMP-PDEs. Various cAMP-PDE inhibitors, mostly cardiotonic compounds, were tested for their inhibitory potency on the different cAMP-PDEs and their selectivity for the type III isoenzyme was determined. Isobutylmethylxanthine, papaverine, theophylline and dipyridamole inhibited PDE activity in a weak and nonselective manner. Milrinone, enoximone, adibendan, pimobendan, bemoridan and the newly synthesized 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline derivatives, R 81267 and R 80122 were selective PDE III inhibitors. However, the IC50 values on this enzyme varied from 10 microM for enoximone to 0.036 microM for R 80122. The selectivity of the drugs for PDE III was calculated by division of the IC50 value for PDE I, II or IV by the IC50 value for PDE III. PDE I/PDE III ratio ranged from 95 for enoximone to near 28,000 for R 80122; the PDE II/PDE III ratios ranged from 95 for enoximone to 3,500 for R 80122. Although there was strong variation between the drugs, most of them showed a high selectivity for PDE III in comparison to PDE I and to PDE II. In contrast, PDE IV appeared to be more sensitive to these substances.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Janssen Research Foundation, Beerse, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: de Cheffoy de Courcelles
authors.forename: K
authors.initials: K
authors.lastname: de Loore
authors.forename: E
authors.initials: E
authors.lastname: Freyne
authors.forename: P A
authors.initials: PA
authors.lastname: Janssen
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007700:Kinetics; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology
chemical_list: D002316:Cardiotonic Agents; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011799:Quinazolines; C076518:R 80122; D015105:3',5'-Cyclic-AMP Phosphodiesterases