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

Naunyn-Schmiedeberg's Archives of Pharmacology
C MartinS Uhlig

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 microM none of the PDE inhibitors significantly affected bronchoconstriction ...Continue Reading

Citations

Jan 6, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Eman M FlefelWafaa A Zaghary
Oct 6, 2007·Experimental Neurology·Coleen M AtkinsW Dalton Dietrich
May 18, 2004·Brain Research. Brain Research Reviews·Kenji HashimotoMasaomi Iyo
Dec 5, 2020·Future Medicinal Chemistry·Oya Unsal Tan, Keriman Ozadali Sari

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