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Inhibition of human cardiac cyclic AMP-phosphodiesterases by R 80122, a new selective cyclic AMP-phosphodiesterase III inhibitor: a comparison with other cardiotonic compounds.
J Pharmacol Exp Ther. 1992 Oct; 263(1):6-14.JP

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+Show Affiliations

Janssen Research Foundation, Beerse, Belgium.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

1328613

Citation

de Cheffoy de Courcelles, D, et al. "Inhibition of Human Cardiac Cyclic AMP-phosphodiesterases By R 80122, a New Selective Cyclic AMP-phosphodiesterase III Inhibitor: a Comparison With Other Cardiotonic Compounds." The Journal of Pharmacology and Experimental Therapeutics, vol. 263, no. 1, 1992, pp. 6-14.
de Cheffoy de Courcelles D, de Loore K, Freyne E, et al. Inhibition of human cardiac cyclic AMP-phosphodiesterases by R 80122, a new selective cyclic AMP-phosphodiesterase III inhibitor: a comparison with other cardiotonic compounds. J Pharmacol Exp Ther. 1992;263(1):6-14.
de Cheffoy de Courcelles, D., de Loore, K., Freyne, E., & Janssen, P. A. (1992). Inhibition of human cardiac cyclic AMP-phosphodiesterases by R 80122, a new selective cyclic AMP-phosphodiesterase III inhibitor: a comparison with other cardiotonic compounds. The Journal of Pharmacology and Experimental Therapeutics, 263(1), 6-14.
de Cheffoy de Courcelles D, et al. Inhibition of Human Cardiac Cyclic AMP-phosphodiesterases By R 80122, a New Selective Cyclic AMP-phosphodiesterase III Inhibitor: a Comparison With Other Cardiotonic Compounds. J Pharmacol Exp Ther. 1992;263(1):6-14. PubMed PMID: 1328613.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of human cardiac cyclic AMP-phosphodiesterases by R 80122, a new selective cyclic AMP-phosphodiesterase III inhibitor: a comparison with other cardiotonic compounds. AU - de Cheffoy de Courcelles,D, AU - de Loore,K, AU - Freyne,E, AU - Janssen,P A, PY - 1992/10/1/pubmed PY - 1992/10/1/medline PY - 1992/10/1/entrez SP - 6 EP - 14 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 263 IS - 1 N2 - 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) SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/1328613/Inhibition_of_human_cardiac_cyclic_AMP_phosphodiesterases_by_R_80122_a_new_selective_cyclic_AMP_phosphodiesterase_III_inhibitor:_a_comparison_with_other_cardiotonic_compounds_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=1328613 DB - PRIME DP - Unbound Medicine ER -