Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 365, Issue 4, pp 284–289

Airway relaxant and anti-inflammatory properties of a PDE4 inhibitor with low affinity for the high-affinity rolipram binding site

  • Christian Martin
  • Rolf Göggel
  • Vittorio Dal Piaz
  • Claudia Vergelli
  • Maria Giovannoni
  • Martin Ernst
  • Stefan Uhlig
Original Article

DOI: 10.1007/s00210-001-0525-7

Cite this article as:
Martin, C., Göggel, R., Dal Piaz, V. et al. Naunyn-Schmiedeberg's Arch Pharmacol (2002) 365: 284. doi:10.1007/s00210-001-0525-7

Abstract.

Inhibitors of phosphodiesterase 4 (PDE4) possess bronchospasmolytic and anti-inflammatory properties, which make them very attractive drugs for the treatment of asthma and COPD. Unfortunately, many PDE4 inhibitors also produce central nervous and gastrointestinal side effects, which have limited their clinical application. PDE4 has two binding sites for the archetypal PDE4 inhibitor rolipram, and it has been suggested that binding to the high-affinity rolipram binding site (HARBS) is responsible for the side effects of PDE4 inhibitors. Recently, we have synthesised the PDE4 inhibitor CC3 which shows low affinity to the HARBS. In the present study we investigated the bronchospasmolytic and anti-inflammatory properties of this novel compound in comparison to rolipram and the PDE3 inhibitor motapizone. The airway-relaxant properties of the PDE inhibitors were analysed in rat precision-cut lung slices (PCLS) in which airways were contracted by methacholine or in passively sensitised PCLS exposed to ovalbumin. The anti-inflammatory properties were investigated by measuring the release of TNF from endotoxin-treated human monocytes.

Up to concentrations of 10 µM none of the PDE inhibitors significantly affected bronchoconstriction elicited by 10 µM methacholine. However, if rolipram or CC3 were given in combination with motapizone, methacholine-induced bronchoconstriction was concentration-dependently attenuated. Allergen-induced bronchoconstriction in passively sensitised PCLS was attenuated by CC3 (IC50 2.7 µM), rolipram (0.23 µM) and motapizone (8 µM). Combination of equimolar concentrations of motapizone and CC3 (0.34 µM) or rolipram (0.005 µM) showed an additive effect. Endotoxin-induced TNF release from human monocytes was attenuated by all three PDE inhibitors, i.e. CC3 (IC50 4.6 µM), rolipram (0.18 µM) and motapizone (5.8 µM). Our findings suggest that PDE4 inhibitors with only low affinity for the HABRS have bronchospasmolytic and anti-inflammatory properties.

Phosphodiesterase 4 Rolipram CC3 Bronchoconstriction Endotoxin TNF Precision-cut lung slice Passive sensitisation 

Copyright information

© Springer-Verlag 2002

Authors and Affiliations

  • Christian Martin
    • 1
  • Rolf Göggel
    • 1
  • Vittorio Dal Piaz
    • 3
  • Claudia Vergelli
    • 3
  • Maria Giovannoni
    • 3
  • Martin Ernst
    • 2
  • Stefan Uhlig
    • 1
  1. 1.Division of Pulmonary Pharmacology, Research Centre Borstel, Parkallee 22, 23845 Borstel, Germany
  2. 2.Division of Cell Biology, Research Centre Borstel, Borstel, Germany
  3. 3.Dipartimento di Scienze Farmaceutiche, via Gino Capponi 9, 50121 Firenze, Italy

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