Comparison of indolidan analog binding sites of drug antibody and sarcoplasmic reticulum with inhibition of cyclic AMP phosphodiesterase

Journal of Receptor and Signal Transduction Research
T AshikagaW J Thompson

Abstract

Dihydropyridazinone(DHP) derivatives such as indolidan are positive inotropic agents that show inhibition of cyclic AMP phosphodiesterase(PDE) activity. Indolidan inhibition is selective for PDE3 among the seven PDE gene families. DHP derivatives and related analogs have been used to define critical regions of the active site of PDE3 isoforms and radiolabeled analogs have been used to define indolidan sarcoplasmic reticulum (SR) receptor sites. We report here studies comparing the structure-activity relationships (SAR) for PDE3 inhibition with indolidan binding to two types of sites: canine SR and a monoclonal antibody derived against indolidan conjugated to a hemocyanin. SR and monoclonal antibody binding both fit singlesite, high affinity models (IC50 = 1.2 and 62 nM) that were near 52 and 360 times that of SR PDE3. Indolidan and thirteen analogs showed similar competition with either SR 3H-LY186126 binding or SR PDE3 inhibition. Antibody binding maintained selectivity but showed a different rank order potency for SR binding. Indole ring C3 methylation increased and DHP ring C4' methylation decreased indolidan monoclonal antibody binding while both substitutions increased SR binding. These studies support the hypothesis that ...Continue Reading

References

Jan 1, 1991·Life Sciences·P W Erhardt, Y L Chou
Jan 1, 1991·Pharmacology & Therapeutics·W J Thompson
Apr 1, 1990·Trends in Pharmacological Sciences·J A Beavo, D H Reifsnyder
Apr 1, 1987·Journal of Cardiovascular Pharmacology·J S HayesD W Robertson
Oct 1, 1987·Journal of Molecular and Cellular Cardiology·R E WeishaarH R Kaplan
Jan 19, 1971·Biochemistry·W J Thompson, M M Appleman
Feb 1, 1993·Pharmacology & Therapeutics·J M Arnold

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