Unique spirocyclopiperazinium salt III: further investigation of monospirocyclopiperazinium (MSPZ) salts as potential analgesics.

Two novel classes of monospirocyclopiperazinium salts were designed, synthesized, and evaluated for their in vivo analgesic activities. Some interesting structure-activity relationships are revealed: (1) Spirocyclopiperazinium moiety is favorable to improve the analgesic activity; (2) The size and conformation of spirocyclopiperazinium moiety significantly affects the analgesic activity; (3) Phenylethyl group of 3d is a crucial pharmacophore. Among the compounds synthesized, 3d exhibited the most potent activity with low toxicity. Further antinociceptive mechanism studies of 3d showed that these compounds will be a new kind of analgesics.

Unique spirocyclopiperazinium salt. Part 4: modification of dispirocyclopiperazinium (DSPZ) salts as analgesics.

In order to improve the analgesic activity of lead compound 7a, two series of dispirocyclopiperazinium (DSPZ) salts 9a-h, 10a-e and compounds 14, 15 were synthesized and evaluated for their in vivo analgesic activity both by acetic acid induced writhing test and hot plate test. Compounds 9h, 14, and 15 exhibited better analgesic activities than 7a. Several important structure-activity relationships were revealed from this study: (1) the introduction of aryl group would obviously improve the activity; (2) it was favorable to enhance the analgesic activity and reduce the toxicity to incorporate alkyl group with suitable length in the molecule; (3) carbamate analogues displayed lower toxicity than carboxylic ester analogues; (4) hydroxylation and chlorination of lead compound could increase the analgesic activity in hot plate test.

[Experimental study on primary pharmacodynamics of Niuhuang Qingwei wan].

OBJECTIVE: To study the primary effects of Niuhuang Qingwei wan on the gastrointestinal function in aninmal for justifying its efficacies in clinic. METHOD: Mice were twice administered with Niuhuang Qingwei wan (0.83, 1.67, 3.33 g x kg(-1), ig) and rats were twice administered with Niuhuang Qingwei wan (0.59, 1.18, 2.36 g x kg(-1), ig). The effects on the stomach function were evaluated by the gastric emptying test in mice and the gastric analysis in rats. The effect on the intestinal function were evaluated by the propulsive motility of the total gastrointestinal tract test in mice by recording the time and frequency of excreting carbo medicinalis. Its analgesia was explored by using the abdominal constriction test induced by acetic acid. RESULT: Niuhuang Qingwei wan decreased the activity and secretion of pepsin in a dose-dependent manner (P < 0.01, P < 0.05), the gastric juice volume at middle and high doses (P <0.01, P <0.05), and the gastric acid volume at high dose (P <0.05); However, it had no significant effects on the gastric emptying in normal mice and the acidity in gastric juice. It shortened the excreting time of feces and increased the frequency of defecation (P < 0.01, P < 0.05). It also inhibited abdominal constriction responses at high dose, and the inhibition rate was 40.0% (P <0.01). CONCLUSION: Niuhuang Qingwei wan can promote gastrointestinal motility, decrease gastric acid volume and activity of pepsin and show certain analgesia effect. Those findings are consistent with its treating stomach heat in clinic.

Antinociceptive effects of the novel spirocyclopiperazinium salt compound LXM-10 in mice.

The compound LXM-10 (2,4-dimethyl-9-beta-phenylethyl-3-oxo-6, 9-diazaspiro [5.5]undecane chloride) is a new spirocyclopiperazinium salt compound. This is the first article to evaluate its antinociceptive effect in the abdominal constriction test induced by acetic acid and the hot-plate test. In the abdominal constriction test, LXM-10 had a significant dose-response effect, and the maximal inhibition ratio was 79.2%. In the hot-plate test, LXM-10 had significant dose-response and time-response effects. The antinociceptive effect began at 1.0 h, peaked at 2.0 h, and persisted 3.0 h after s.c. administration. The hot-plate latency was increased by 126.8% at the dose of 12.0 mg/kg. The antinociceptive effect of LXM-10 was blocked by mecamylamine (a central and peripheral neuronal nicotinic acetylcholine receptor antagonist, 0.25, 0.5, 1.0 mg/kg, i.p.), hexamethonium (a peripheral neuronal nicotinic acetylcholine receptor antagonist, 0.2, 1.0, 5.0 mg/kg, i.p.), atropine (a central and peripheral muscarinic acetylcholine receptor antagonist, 0.2, 1.0, 5.0 mg/kg, i.p.), and atropine methylnitrate (a peripheral muscarinic acetylcholine receptor antagonist, 0.2, 1.0, 5.0 mg/kg, i.p.) in a dose-dependent fashion. In contrast, the effect was not blocked by naloxone (a non-selective opioid receptor antagonist, 2.0 mg/kg, i.p.) or yohimbine (a alpha(2)-adrenergic receptor antagonist, 1.0, 2.5, 5.0 mg/kg, i.p.) in the hot-plate test. Therefore, the antinociceptive effects of LXM-10 involve the peripheral neuronal nicotinic and muscarinic acetylcholine receptors; they are not related to opioid receptors or alpha(2)-adrenergic receptors. LXM-10 did not affect motor coordination, spontaneous activity, or body temperature. These findings with LXM-10 suggest that spirocyclopiperazinium derivatives could provide insight on new analgesics.