1-[N,O-二(5-异喹啉磺酰基)-N-甲基-L-型酪氨酸]-4-苯基哌嗪

IC50: 0.9 μM (CaMK II), 15 nM (P2X ₇ receptor, in HEK293 cells)

KN-62 is a selective antagonist of Ca ²⁺ /calmodulin-dependent protein kinase II (CaMKII). KN-62 potently antagonizes ATP-stimulated Ba ²⁺ influx into fura-2 loaded human lymphocytes with an IC ₅₀ of 12.7±1.5 nM (n=3) and complete inhibition of the flux at a concentration of 500 nM. Similarly, KN-62 inhibits ATP-stimulated ethidium ⁺ uptake, measured by time resolved flow cytometry, with an IC ₅₀ of 13.1±2.6 nM (n=4) and complete inhibition of the flux at 500 nM. KN-62 is found to be a potent antagonist in a functional assay, inhibition of ATP-induced K ⁺ efflux in HEK293 cells expressing recombinant human P2X ₇ receptors. In human leukemic B lymphocytes, KN-62 reduces the rate of permeability increase to larger permeant cations, like ethidium, induced by Bz-ATP with an IC ₅₀ of 13.1 nM. KN-62 at a concentration of 3 µM has no effect on ATP-induced ethidium influx through the rat P2X ₇ receptor, while the IC ₅₀ at the human P2X ₇ receptor is 0.1 µM. KN-62 has considerable selectivity for P2X ₇ receptors within the P2 family.

The antidepressant-like behavior of ZnCl ₂ (10 mg/kg, p.o.) (p<0.01) is prevented by CAMKII inhibitor KN-62 (1 μg/site, i.c.v.). The two-way ANOVA reveals a significantly main effect of KN-62 treatment [F(1,28)=27.47, p<0.01], no main effect of ZnCl ₂ treatment [F(1,28)=0.84, p>0.05] and a significant effect of KN-62×ZnCl ₂ treatment interaction [F(1,28)=22.57, p<0.01] to immobility time. As revealed by the post-hoc analysis, the anti-immobility effect of ZnCl ₂ is completely prevented by treatment of animals with KN-62. No effect in locomotor activity in the open-field test is observed: (KN-62 treatment [F(1,24)=1.97, p>0.05], ZnCl ₂ treatment [F(1,24)=3.99, p>0.05] and KN-62×ZnCl ₂ treatment interaction [F(1,24)=0.61, p>0.05]).