UNEXPECTED NEUROPROTECTION OBSERVED WITH THE ADENOSINE A(2A) RECEPTORAGONIST CGS-21680

The selective adenosine A(2A) receptor agonists )phenylethylamino]-5'- N-ethylcarboxyamidoadenosine (CGS 21680), N-[2-(3,5-dimethoxyphenyl)et hyl]adenosine (DPMA) and metrifudil were investigated for their abilit y to prevent the loss of pyramidal CA1 neurons in the hippocampus foll owing 5 min of severe temporary forebrain ischemia in mongolian gerbil s. CGS 21680, when administered at 18.7 mu mol/kg 30 and 120 min follo wing reperfusion, exhibited highly significant protection against neur onal loss, but was inactive at 5.6 mu mol/kg. DPMA, a more potent agon ist at A(1) and A(2A) receptors, was inactive up to a dose of 19 mu mo l/kg. Metrifudil (equipotent with CGS 21680 at A(2A) > 25 times more p otent at A(1)) gave a modest degree of protection at 26 mu mol/kg and was inactive at 7.8 mu mol/kg. CCS 21680 showed an equal degree of hyp othermia at 5.6 and 18.7 mu mol/kg, suggesting that this was not the p rime mode of action. While the effect of metrifudil may be the result of its higher A(1) receptor affinity, the mode of action of CCS 21680 has not been established; the data, however, suggest that a non-A(1) n on-A(2A) receptor mechanism may possibly be involved. (C) 1997 Wiley-L iss, Inc.