PMID- 11919652
OWN - NLM
STAT- MEDLINE
DCOM- 20020918
LR  - 20141120
IS  - 0028-1298 (Print)
IS  - 0028-1298 (Linking)
VI  - 365
IP  - 4
DP  - 2002 Apr
TI  - Airway relaxant and anti-inflammatory properties of a PDE4 inhibitor with low 
      affinity for the high-affinity rolipram binding site.
PG  - 284-9
AB  - 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 elicited by 10 microM 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 (IC(50) 2.7 microM), rolipram (0.23 microM) and motapizone (8 
      microM). Combination of equimolar concentrations of motapizone and CC3 (0.34 
      microM) or rolipram (0.005 microM) showed an additive effect. Endotoxin-induced 
      TNF release from human monocytes was attenuated by all three PDE inhibitors, i.e. 
      CC3 (IC(50) 4.6 microM), rolipram (0.18 microM) and motapizone (5.8 microM). Our 
      findings suggest that PDE4 inhibitors with only low affinity for the HABRS have 
      bronchospasmolytic and anti-inflammatory properties.
FAU - Martin, Christian
AU  - Martin C
AD  - Division of Pulmonary Pharmacology, Research Centre Borstel, Parkallee 22, 23845 
      Borstel, Germany.
FAU - Goggel, Rolf
AU  - Goggel R
FAU - Dal Piaz, Vittorio
AU  - Dal Piaz V
FAU - Vergelli, Claudia
AU  - Vergelli C
FAU - Giovannoni, Paola
AU  - Giovannoni P
FAU - Ernst, Martin
AU  - Ernst M
FAU - Uhlig, Stefan
AU  - Uhlig S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20020227
PL  - Germany
TA  - Naunyn Schmiedebergs Arch Pharmacol
JT  - Naunyn-Schmiedeberg's archives of pharmacology
JID - 0326264
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Phosphodiesterase Inhibitors)
RN  - 0 (Pyrrolidinones)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.1.4.17 (3',5'-Cyclic-AMP Phosphodiesterases)
RN  - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4)
RN  - K676NL63N7 (Rolipram)
SB  - IM
MH  - 3',5'-Cyclic-AMP Phosphodiesterases/*antagonists & inhibitors/*metabolism
MH  - Animals
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Binding, Competitive
MH  - Bronchoconstriction/*drug effects
MH  - Cyclic Nucleotide Phosphodiesterases, Type 4
MH  - Female
MH  - In Vitro Techniques
MH  - Lipopolysaccharides/pharmacology
MH  - Monocytes/drug effects/metabolism
MH  - Phosphodiesterase Inhibitors/*pharmacology
MH  - Pyrrolidinones/*pharmacology
MH  - Rats
MH  - Rats, Wistar
MH  - Rolipram/pharmacology
MH  - Tumor Necrosis Factor-alpha/metabolism
EDAT- 2002/03/29 10:00
MHDA- 2002/09/19 10:01
CRDT- 2002/03/29 10:00
PHST- 2001/07/04 00:00 [received]
PHST- 2001/12/07 00:00 [accepted]
PHST- 2002/03/29 10:00 [pubmed]
PHST- 2002/09/19 10:01 [medline]
PHST- 2002/03/29 10:00 [entrez]
AID - 10.1007/s00210-001-0525-7 [doi]
PST - ppublish
SO  - Naunyn Schmiedebergs Arch Pharmacol. 2002 Apr;365(4):284-9. doi: 
      10.1007/s00210-001-0525-7. Epub 2002 Feb 27.