Zatosetron maleate

Glycine receptors (GlyRs) were studied via [(3)H]strychnine binding to synaptosomal membranes of rat spinal cord. A ternary allosteric model was applied for the effects of tropeines, alcohols, minaxolone, nitrendipine, Zn(2+), muscarinic and serotonin receptor ligands. It enabled us to determine the dissociation constants of the allosteric agents (K(A)) and their cooperativity factors affecting the dissociation constants of [(3)H]strychnine (alphaK(S)) and glycine (betaK(L)). Cooperativity with [(3)H]strychnine ranged from strong negative for tropeines to weak positive for nitrendipine. Displacement curves of glycine were examined in the presence of allosteric agents. Positive cooperativities with glycine were found for submicromolar concentrations of tropisetron, bemesetron, zatosetron and nitrendipine; for tubocurarine, propofol, butanol, minaxolone, cocaine and 10 microM Zn(2+). Micromolar concentrations of tropisetron and nitrendipine showed weaker cooperativities. Other allosteric agents and 1 mM Zn(2+) displayed negative cooperativity with glycine. Binding parameters K(A) and beta correlate excellently with the activities of the allosteric agents on GlyR-ionophores. Combined inhibitory effects of the allosteric agents suggest that there are different subgroups (tropeines, alcohols and dihydropyridines) binding to distinct sites on GlyRs exerting cooperativity with glycine via a common mechanism. This is the first quantitative analysis of allosteric binding interactions for GlyRs.

Previous studies have suggested that the alpha2-adrenergic receptor antagonist yohimbine produced antinociceptive effects in the formalin test in rats. However, yohimbine is also an agonist at serotonin (5-HT)1A receptors, suggesting the possibility that the antinociceptive effects of yohimbine might be mediated via these receptors.

The purpose of the present studies was to evaluate the potential role of 5-HT(1A) receptors in mediating the antinociceptive effects of yohimbine.

The antinociceptive effects of yohimbine were evaluated using the formalin test in rats.

Yohimbine (2.5-10 mg/kg s.c.) produced dose-related antinociception during both phase I and phase II of the formalin test, and was approximately equipotent and equiefficacious to morphine. The selective 5-HT(1A) receptor antagonist WAY 100,635 (0.03-3.0 mg/kg s.c.) produced a partial reversal of yohimbine. In comparison, the selective 5-HT(1A) receptor agonist (+/-)8-hydroxy-dipropylaminotetralin HBr (8OH-DPAT; 1.0 mg/kg s.c.) also produced a dose-related antinociception in the formalin test, although 8OH-DPAT was completely reversed by WAY 100,635 (3.0 mg/kg s.c.). The antinociceptive effects of yohimbine were not antagonized by the 5-HT(1B/1D) antagonist GR 127935 (1.0 mg/kg and 3.0 mg/kg s.c.), the 5-HT2 antagonist LY53857 (1.0 mg/kg s.c.), or the 5-HT3 antagonist zatosetron (3.0 mg/kg s.c.).

The present results demonstrate that yohimbine produces a dose-related antinociception in the formalin test in rats which is mediated in part by the agonistic actions at 5-HT(1A) receptors.