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

Abstract

[3H]Cimetidine, a radiolabeled histamine H2 receptor antagonist, binds with high affinity to an unknown hemoprotein in the brain which is not the histamine H2 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 [3H]cimetidine-binding site is the improgan antinociceptive target, improgan, cimetidine, and 8 other chemical congeners were studied as potential inhibitors of [3H]cimetidine binding in membrane fractions from the rat brain. All compounds produced a concentration-dependent inhibition of [3H]cimetidine binding over a 500-fold range of potencies (Ki values were 14.5 to >8,000 nM). However, antinociceptive potencies in rats did not significantly correlate with [3H]cimetidine-binding affinities (r = 0.018, p = 0.97, n = 10). These results suggest that the [3H]cimetidine-binding site is not the analgesic target for improgan-like drugs.

Opioid Analgesia in P450 Gene Cluster Knockout Mice: A Search for Analgesia-Relevant Isoforms

“…Since inhibitors of 3 HCIM binding also block the effects of several types of analgesics, 3 HCIM-binding proteins were suggested to be targets for analgesic drug development (Hough et al, 2007;Stadel et al, 2010). The absence of deficits in 3 HCIM binding in liver homogenates from the genotypes studied (Supplemental Fig.…”

“…Identification of these proteins is of interest because they could be new analgesic drug targets (Hough et al, 2007). Although this idea has not been confirmed (Stadel et al, 2010), 3 HCIM-binding studies led to the discovery that the painrelieving effects of both nonopioid (Hough et al, 2011) and opioid (Conroy et al, 2010) analgesic drugs require brain P450 activity.…”