LXM-10

Anti-inflammatory drugs are clinically limited because of their side effects. The aim of this study was to evaluate the anti-inflammatory activities and mechanisms of the spirocyclopiperazinium compound LXM-10 (2, 4-dimethyl-9-beta-phenylethyl-3-oxo-6, 9-diazaspiro[5.5]undecane chloride). We found that LXM-10 produced a significant, dose-dependent decrease in xylene- and carrageenin-induced edema. The anti-inflammatory effect was attenuated by hexamethonium, methyllycaconitine citrate, atropine methylnitrate, and tropicamide. The serum level of TNF-alpha was reduced by LXM-10 in lipopolysaccharide-challenged mice, and this effect was also inhibited by methyllycaconitine and tropicamide. LXM-10 also reduced the prostaglandin E(2) concentration in rat paw tissue. LXM-10 minimised the carrageenin-induced pathological changes and did not affect mice heart rate. LXM-10 did not induce significant changes in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP) activity. Median lethal dose (LD(50)) of LXM-10 was 1573.0 micromol/kg. Our findings suggest that LXM-10 has anti-inflammatory effects by activating alpha7 nicotinic and M(4) muscarinic acetylcholine receptors with limited side effects.

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.