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Related Experiment Videos

Modulators of cyclic AMP systems.

S M Hess, M Chasin, C A Free

    Advances in Biochemical Psychopharmacology
    |January 1, 1975
    PubMed
    Summary

    Many drugs affecting the central nervous system modulate cyclic AMP, but a direct link to their pharmacologic activity is difficult to establish. Unexpectedly, numerous agents inhibit phosphodiesterase (PDE), a finding useful for drug discovery.

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    Area of Science:

    • Pharmacology
    • Neuroscience
    • Biochemistry

    Background:

    • Many central nervous system (CNS) agents are known modulators of cyclic adenosine monophosphate (cAMP).
    • Establishing a direct correlation between the pharmacologic activity of these agents and brain cAMP levels has proven challenging.
    • This difficulty extends to benzodiazepines and pyrazolopyridines, despite some correlations observed in specific assays.

    Purpose of the Study:

    • To investigate the relationship between the pharmacologic activity of various agents and their effects on cyclic AMP levels in the brain.
    • To explore the mechanisms by which phosphodiesterase (PDE) inhibitors influence cAMP levels in CNS tissues and platelets.
    • To assess the prevalence of PDE inhibition among pharmacologic agents as a potential drug discovery tool.

    Main Methods:

    • Assessed the correlation between phosphodiesterase (PDE) inhibition potency and antianxiety test activity for pyrazolopyridines.
    • Measured steroidogenesis in isolated adrenal cells and correlated it with activity in the conflict assay.
    • Investigated the effects of PDE inhibitors (e.g., papaverine, chlordiazepoxide, theophylline) on cAMP levels in guinea pig brain slices and platelet aggregation.

    Main Results:

    • A strong correlation was found between PDE inhibition and antianxiety effects for pyrazolopyridines, and between in vitro activity and conflict assay results for steroidogenesis.
    • Agents inhibiting PDE in cell-free systems influenced cAMP levels in brain slices through mechanisms independent of direct PDE inhibition, potentially involving agonist release.
    • Platelet studies showed clear inhibition of aggregation with increased cAMP levels, suggesting potent PDE inhibitors potentiate prostaglandin E1 (PGE1) effects.

    Conclusions:

    • A direct mechanistic link between modulation of cyclic AMP (cAMP) and the pharmacologic activity of many CNS-acting agents remains difficult to establish.
    • Mechanisms of action for tested drug classes are not solely attributable to cAMP modulation.
    • An unexpectedly high proportion of pharmacologic agents were found to be phosphodiesterase (PDE) inhibitors, presenting a valuable resource for drug discovery.

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