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 (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.