Inhibition of brain [3H]cimetidine binding by improgan-like antinociceptive drugs

Abstract [ 3 H]cimetidine, a radiolabeled histamine H 2 receptor antagonist, binds with high affinity to an unknown hemoprotein in the brain which is not the histamine H 2 receptor. Improgan, a close chemical congener of cimetidine, is a highly effective pain-relieving drug following CNS administration, yet its mechanism of action remains unknown. To test the hypothesis that the [ 3 H]cimetidine-binding site is the improgan antinociceptive target, improgan, cimetidine, and 8 other chemical congeners were studied as potential inhibitors of [ 3 H]cimetidine binding in membrane fractions from the rat brain. All compounds produced a concentration-dependent inhibition of [ 3 H]cimetidine binding over a 500-fold range of potencies ( K i values were 14.5 to > 8000 nM). However, antinociceptive potencies in rats did not significantly correlate with [ 3 H]cimetidine-binding affinities ( r  = 0.018, p  = 0.97, n  = 10). These results suggest that the [ 3 H]cimetidine-binding site is not the analgesic target for improgan-like drugs.