Association of the anti-inflammatory activity of phosphodiesterase 4 (PDE4) inhibitors with either inhibition of PDE4 catalytic activity or competition for [ 3H]rolipram binding

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 (TNFa) formation] or suppression of neutrophil activation (degranulation) with inhibition of either PDE4 catalytic activity or [ 3H]rolipram binding. Suppression of TNFa 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 [H]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.