The effects of the anti-inflammatory and
analgesic drug 3-ethyl-1-(3-nitrophenyl)-2,4[1H, 3H]-quinazolindione (
TVX 2706) on neuronal and glial cell culture systems including
neuroblastoma X
glioma hybrid cells have been studied. This compound strongly enhances the increase in intracellular levels of
cyclic AMP caused by appropriate effectors in all systems tested so far. EC50 values are in the submicromolar range. The effect is apparently neither due to an increased responsiveness of the hybrid cells for an effector like
prostaglandin E1 nor to an increased activity of
adenylate cyclase, but to an inhibition of both low and high affinity
cyclic AMP phosphodiesterases. Half-maximal inhibition of
enzyme activity is obtained
at 10 microM
TVX 2706. The
drug is at least equipotent to or more potent than some other common
phosphodiesterase inhibitors. Inhibition of
phosphodiesterase activity is also observed in homogenates from rat polymorphonuclear leucocytes, where the low Km-
enzyme is preferentially inhibited.
TVX 2706 does not interfere with the
calmodulin activation of
phosphodiesterase. The role of
phosphodiesterase inhibition as a possible mechanism of the anti-inflammatory action of
TVX 2706 is discussed.