piperidines and loxtidine

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.

Topics: Algorithms; Analgesics; Animals; Behavior, Animal; Benzothiazoles; Brain; Cimetidine; Dose-Response Relationship, Drug; Histamine H2 Antagonists; Injections, Intraventricular; Male; Mice; Molecular Structure; Pain; Pain Measurement; Phenoxypropanolamines; Piperidines; Quinazolines; Quinazolinones; Rats; Rats, Sprague-Dawley; Thiazoles; Time Factors; Triazoles

Histamine H2 receptor-mediated responses were examined on cholecystokinin-octapeptide (CCK-8)-precontracted guinea pig gallbladder in vitro, testing histamine and a series of specific histamine H2 receptor agonists and antagonists. Among the antagonists tested, zolantidine and compound SKF 92857 were previously shown to antagonize H2 receptor-mediated responses in the heart, but not in the stomach. Histamine, in the presence of the H2 receptor antagonist mepyramine (10 microM), and the H2 receptor agonists dimaprit, impromidine and amthamine, inhibited CCK-8 (3 nM)-induced contractions in a concentration-dependent fashion, with the following rank orders of potency: impromidine > amthamine > histamine > dimaprit (pD2 values were 6.73 +/- 0.04, 5.44 +/- 0.07, 4.64 +/- 0.04 and 3.71 +/- 0.05, respectively). The maximal relaxation produced by dimaprit was significantly lower than that produced by histamine, as well as by impromidine and amthamine, which behaved as full agonists. All the H2 receptor antagonists examined were able to inhibit amthamine-induced relaxation. Famotidine (pA2 = 7.09 +/- 0.26), zolantidine (pA2 = 6.54 +/- 0.11), compound SKF 92857 (pA2 = 6.58 +/- 0.13) and aminopotentidine (pA2 = 6.86 +/- 0.06) competitively antagonised the amthamine-induced effect, while iodoaminopotentidine produced surmountable antagonism only at low concentrations (1 microM, pA2 = 6.83 +/- 0.21). Finally, the slowly-dissociable antagonist loxtidine caused a non-parallel displacement to the right of the concentration--response curve to amthamine (pKB = 7.55 +/- 0.24), with a significant depression of the maximal response to the agonist, even at the lowest effective concentration (0.3 microM). In conclusion, histamine H2 receptors in guinea pig gallbladder resemble those of the heart, as regards their sensitivity to zolantidine and compound SKF 92857, which, by contrast, were unable to antagonize histamine effects at gastric H2 receptors in different experimental models.

Topics: Animals; Benzothiazoles; Dopamine Agents; Famotidine; Gallbladder; Guanidines; Guinea Pigs; Histamine; Histamine Agonists; Histamine H2 Antagonists; In Vitro Techniques; Male; Muscle Contraction; Muscle Relaxation; Phenoxypropanolamines; Piperidines; Pyridines; Receptors, Histamine H2; Sincalide; Thiazoles; Triazoles

The effect of the selective H3 receptor agonist (R)-alpha-methylhistamine and antagonist thioperamide on water consumption in the rat were examined. (R)-alpha-Methylhistamine (0.1-20 mg.kg-1 i.p.) evoked a dose-dependent increase in water consumption the maximum effect being 310 +/- 23% (n = 67) above the vehicle control response. Thioperamide (0.2,2 and 10 mg.kg-1 i.p.) alone had no effect on water consumption. However, the stimulatory effect of (R)-alpha-methylhistamine on water consumption was antagonised by thioperamide in a dose-dependent manner, whereas the H1 receptor antagonist mepyramine and the H2 receptor antagonist loxtidine were without effect. It is therefore concluded that the H3 receptor may play a role in the regulation of water consumption in the rat.

Topics: Animals; Drinking; Histamine; Histamine Antagonists; Male; Methylhistamines; Nicotinic Acids; Piperidines; Pyrilamine; Rats; Receptors, Histamine; Receptors, Histamine H3; Tetrazoles; Triazoles