m-chlorophenylguanidine and Pain

MD-354 (meta-chlorophenylguanidine) has been identified as a member of a novel class of 5-HT(3) serotonin receptor agonists. MD-354 is a 5-HT(3) receptor partial agonist that has been shown to behave as an agonist in some assays, and as an antagonist in others. MD-354 also binds at alpha-adrenoceptors (ARs) and displays an affinity for alpha(2B)-ARs comparable to its affinity for 5-HT(3) receptors. Although devoid of antinociceptive actions following systemic administration alone, MD-354 markedly enhances the antinociceptive actions of clonidine in the mouse tail-flick assay without potentiating the sedative side effects of clonidine. Although studies with MD-354 are still in progress, some pharmacological findings are described here. MD-354-related agents may represent drug adjuvants for the relief of severe pain.

Topics: Analgesics; Animals; Clonidine; Dose-Response Relationship, Drug; Drug Synergism; Guanidines; Humans; Mice; Pain; Pain Measurement; Serotonin Receptor Agonists

Previously, we reported that antinociceptive synergism of a 5-HT(3)/alpha(2)-adrenoceptor ligand MD-354 (m-chlorophenylguanidine) and clonidine combination occurs, in part, through a 5-HT(3) receptor antagonist mechanism. In the present investigation, a possible role for alpha(2)-adrenoceptors was examined. Mechanistic studies using yohimbine (a subtype non-selective alpha(2)-adrenoceptor antagonist), BRL 44408 (a preferential alpha(2A)-adrenoceptor antagonist) and imiloxan (a preferential alpha(2B/C)-adrenoceptor antagonist) on the antinociceptive actions of a MD-354/clonidine combination were conducted. Subcutaneous pre-treatment with all three antagonists inhibited the antinociceptive synergism of MD-354 and clonidine in the mouse tail-flick assay in a dose-dependent manner (AD(50) = 0.33, 2.1, and 0.17 mg/kg, respectively). Enhancement of clonidine antinociception by MD-354 did not potentiate clonidine's locomotor suppressant activity in a mouse locomotor assay. When [ethyl-3H]RS-79948-197 was used as radioligand, MD-354 displayed almost equal affinity to alpha(2A)- and alpha(2B)-adrenoceptors (K(i) = 110 and 220 nM) and showed lower affinity at alpha(2C)-adrenoceptors (K(i) = 4,700 nM). MD-354 had no subtype-selectivity for the alpha(2)-adrenoceptor subtypes as an antagonist in functional [35S]GTPgammaS binding assays. MD-354 was a weak partial agonist at alpha(2A)-adrenoceptors. Overall, in addition to the 5-HT(3) receptor component, the present investigation found MD-354 to be a weak partial alpha(2A)-adrenoceptor agonist that enhances clonidine's thermal antinociceptive actions through an alpha(2)-adrenoceptor-mediated mechanism without augmenting sedation.

Topics: Adrenergic alpha-Antagonists; Analgesics; Animals; Behavior, Animal; Clonidine; Drug Synergism; Guanidines; Imidazoles; Injections, Subcutaneous; Isoindoles; Male; Mice; Mice, Inbred ICR; Motor Activity; Pain; Pain Measurement; Receptors, Adrenergic, alpha; Tail; Yohimbine

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