The antinociceptive profile of selected
histamine H(2) and
histamine H(3) receptor antagonists led to the discovery of
improgan, a non-brain-penetrating
analgesic agent which does not act on known
histamine receptors. Because no chemical congener of
improgan has yet been discovered which has both antinociceptive and brain-penetrating properties, the present study investigated the antinociceptive effects of a series of chemical compounds related to
zolantidine, a brain-penetrating
histamine H(2) receptor antagonist. The drugs studied presently contain the piperidinomethylphenoxy (PMPO) moiety, hypothesized to introduce brain-penetrating characteristics. Following intracerebroventricular (i.c.v.) dosing in rats, six of eight drugs produced dose- and time-related antinociception on both the tail flick and hot plate tests over a nearly eight-fold range of potencies.
Ataxia and other motor side effects were observed after high doses of these drugs, but two of the compounds (SKF94674 and
loxtidine) produced maximal antinociception at doses which were completely devoid of these motor effects. Consistent with the hypothesis that PMPO-containing drugs are brain-penetrating
analgesics, SKF94674 and another derivative (JB-9322) showed dose-dependent antinociceptive activity 15 to 30 min after systemic dosing in mice, but these effects were accompanied by
seizures and death beginning 45 min after dosing. Other drugs showed a similar pattern of antinociceptive and toxic effects. In addition,
loxtidine produced
seizures without antinociception, whereas
zolantidine produced neither effect after systemic dosing in mice. Although several of the drugs tested have
histamine H(2) receptor antagonist activity, neither the antinociception nor the toxicity was correlated with
histamine H(2) receptor activity. The present results are the first to demonstrate the existence of brain-penetrating
antinociceptive agents chemically related to
zolantidine and
improgan, but further studies are needed to understand the mechanisms of both the
pain relief and toxicity produced by these agents.