TVX 2706--a new phosphodiesterase inhibitor with antiinflammatory action. Biochemical characterization.
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.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006822:Hybrid Cells; D007700:Kinetics; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010726:Phosphodiesterase Inhibitors; D011799:Quinazolines; C044248:nitraquazone; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000262:Adenylyl Cyclases