m-chlorophenylguanidine and zacopride

MD-354 (m-chlorophenylguanidine) is a 5-HT3/alpha2B-adrenoceptor ligand. Both receptors play a role in antinociception. In the mouse tail-flick assay, subcutaneously administered MD-354 was inactive as an analgesic. However, a combination of an inactive dose of clonidine (0.25 mg/kg) with an inactive dose of MD-354 (6 mg/kg) produced a substantial antinociceptive effect (maximal possible effect=66%). Considering the 5-HT3 receptor partial agonist properties of MD-354, the analgesia enhancing effect of MD-354 on clonidine might be associated, at least in part, with its 5-HT3 receptor agonist or antagonist activity. Combinations of an inactive dose of clonidine (0.25 mg/kg) with 5-HT3 receptor antagonists (tropisetron, zacopride and ondansetron) were examined. Saline-like doses of tropisetron, zacopride and ondansetron significantly enhanced the antinociceptive effect of clonidine (combinations: maximal possible effect=86%, 82% and 79% respectively), suggesting that MD-354 may enhance the analgesic actions of clonidine, at least in part, through a 5-HT3 receptor antagonist mechanism.

Topics: Analgesics; Animals; Behavior, Animal; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Clonidine; Dose-Response Relationship, Drug; Drug Synergism; Guanidines; Indoles; Male; Mice; Mice, Inbred ICR; Models, Animal; Motor Activity; Ondansetron; Pain; Pain Measurement; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Time Factors; Tropisetron

Albeit conflicting, evidence suggests that 5-HT3 receptor partial agonists as well as alpha2NON-A-adrenoceptor agonists might be involved in antinociception. MD-354 (m-chlorophenylguanidine) can be viewed as the first example of a rather selective 5-HT3/alpha2B-adrenergic ligand. In a tail-flick test in mice, subcutaneous administration of MD-354 doses up to 30 mg/kg did not produce antinociception and failed to antagonize the effect of clonidine (ED50=0.5 mg/kg), but a combination of an inactive de of clonidine (0.25 mg/kg) that produced only 13% maximal possible effect (MPE) with an inactive dose of MD-354 (10 mg/kg, MPE=8%) produced an antinociceptive effect (MPE=83%). In the hot-plate assay, neither subcutaneous administration of MD-354 (3 to 30 mg/kg) alone nor in combination with clonidine (ED50=0.8 mg/kg) produced an antinociceptive effect. MD-354 was demonstrated to potentiate the antinociceptive effect of clonidine in the tail-flick assay, but its underlying mechanism remains to be determined.

Topics: Analgesics; Animals; Benzamides; Binding, Competitive; Bridged Bicyclo Compounds, Heterocyclic; Clonidine; Dose-Response Relationship, Drug; Drug Synergism; Guanidines; Mice; Mice, Inbred ICR; Morphine; Pain; Pain Measurement; Radioligand Assay; Receptor, Serotonin, 5-HT1A; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, alpha-2; Receptors, Serotonin