Studies on mechanisms of low emetogenicity of YM976, a novel phosphodiesterase type 4 inhibitor

YM976 is a novel and selective inhibitor of phosphodiesterase type 4 (PDE4) with a different chemical structure from rolipram. Orally administered YM9 76 showed anti-inflammatory activity (ED50 = 2.8 mg/kg) similar to rolipram (3.5 mg/kg). On the other hand, the emetogenicity of YM976, one of the mai n adverse effects of PDE4 inhibitors, was lower (maximal non-emetic dose = 10 mg/kg) than that of rolipram (1 mg/kg). The reasons for this low emetoge nicity of YM976 remain unclear, and the present study endeavored to elucida te the mechanisms. Candidates for the possible mechanisms included 1) PDE4 subtype selectivity, 2) binding affinity for HAR-conformation, and 3) brain penetration. YM976 exhibited affinity for high affinity for rolipram-confo rmation (HAR-conformation) (IC50 = 2.6 nM) identical to that of rolipram (1 .2 nM), and failed to show significant selectivity for the individual PDE4 subtype. These results suggested that neither subtype selectivity nor the a ffinity for HAR-conformation may be related to the low emetogenicity of YM9 76. YM976 showed a minor effect on reserpine-induced hypothermia, in contra st to rolipram. To estimate brain penetration, we then measured cAMP conten ts in peripheral tissues (peritoneal macrophages) and in the brain. YM976 i ncreased the cAMP content of peritoneal macrophages, but caused no signific ant increase in brain cAMP levels, while rolipram elevated the cAMP content of both tissues at the same dose. In conclusion, YM976 shows an apparent d issociation between its anti-inflammatory effects and emetogenicity, perhap s because of the poor brain penetration.