title: Association of the anti-inflammatory activity of phosphodiesterase 4 (PDE4) inhibitors with either inhibition of PDE4 catalytic activity or competition for [3H]rolipram binding.
abstract: Phosphodiesterase 4 (PDE4) inhibitors are novel anti-inflammatory compounds. Unfortunately, the archetypal PDE4 inhibitor rolipram produces central nervous system and gastrointestinal side-effects. To exploit these agents, we need to identify PDE4 inhibitors that retain the anti-inflammatory activity with a reduced potential to elicit unwanted side-effects. PDE4 possesses both cyclic AMP catalytic activity that is inhibitable by rolipram and a high affinity binding site for rolipram. The function of this high affinity rolipram binding site is unclear; however, certain pharmacological effects of PDE4 inhibitors are associated with competition for this site. Since PDE4 inhibitors suppress both monocyte and neutrophil activation, the present experiments were carried out to establish a correlation between suppression of monocyte activation [tumor necrosis factor alpha (TNF alpha) formation] or suppression of neutrophil activation (degranulation) with inhibition of either PDE4 catalytic activity or [3H] rolipram binding. Suppression of TNF alpha formation demonstrated a strong correlation with inhibition of PDE4 catalytic activity (r=0.87; P<0.01; Spearman's Rho = 0.79, P<0.05), whereas there was no correlation with inhibition of [3H]rolipram binding(r=0.21, P>0.5; Spearman's Rho=0.16, P>0.5). Suppression of neutrophil degranulation was not associated with inhibition of PDE4 catalytic activity (r=0.25, P>0.4; Spearman's Rho=0.33, P>0.2), but was associated with inhibition of [3H]rolipram binding (r=0.68, P<0.05; Spearman's Rho=0.6, P=0.06). These results indicate that anti-inflammatory effects of PDE4 inhibitors can be associated with either inhibition of PDE4 catalytic activity or high affinity rolipram binding.
authors.affiliation: Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Barnette
authors.forename: J O
authors.initials: JO
authors.lastname: Bartus
authors.forename: M
authors.initials: M
authors.lastname: Burman
authors.forename: S B
authors.initials: SB
authors.lastname: Christensen
authors.forename: L B
authors.initials: LB
authors.lastname: Cieslinski
authors.forename: K M
authors.initials: KM
authors.lastname: Esser
authors.forename: U S
authors.initials: US
authors.lastname: Prabhakar
authors.forename: J A
authors.initials: JA
authors.lastname: Rush
authors.forename: T J
authors.initials: TJ
authors.lastname: Torphy
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D006801:Humans; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D011760:Pyrrolidinones / Q000494:pharmacology*; D011869:Radioligand Assay; D020889:Rolipram; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011760:Pyrrolidinones; D014409:Tumor Necrosis Factor-alpha; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram