Antinociceptive synergism of MD-354 and clonidine. Part II. The alpha-adrenoceptor component.
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.
Young
Shawquia
S
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA.
Vainio
Minna
M
Scheinin
Mika
M
Dukat
Małgorzata
M
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology*; D004357:Drug Synergism; D006146:Guanidines / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D007279:Injections, Subcutaneous; D054833:Isoindoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism; D013623:Tail / Q000294:innervation; D015016:Yohimbine / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D000700:Analgesics; D006146:Guanidines; D007093:Imidazoles; D054833:Isoindoles; D011942:Receptors, Adrenergic, alpha; C495409:m-chlorophenylguanidine; D015016:Yohimbine; D003000:Clonidine; C072125:BRL 44408; C044484:Imiloxan