A compound structurally related to
clonidine, N,N-dimethyl-N'-(2,4, 6-trimethyl phenyl)formamidine hydrochloride (U-47,476A), was evaluated for
analgesic activity; it produced a significant
analgesia in mice and rats in several analgesiometric procedures. The
analgesic potency varied considerably with different analgesiometric tests, with ED50s ranging from 0.4 mg/kg for writhing in mice induced by
hydrochloric acid to greater than 30 mg/kg for the tail-flick test in rats. Although the potency was less than that of
clonidine, it was still in the range of
pentazocine. Then
U-47,476A was further examined to determine whether the
analgesic effect was mediated by alpha-
adrenergic mechanisms and accompanied by
hypotension and sedation, similar to that produced by
clonidine. The
drug U-47,476A failed to lower significantly blood pressure in rats given 10 and 30 mg/kg subcutaneously, suggesting a possible separation of the hypotensive and
analgesic properties of this compound. The locomotor activity of mice was unaltered after 0.5 mg/kg of U-47,476A; however, a significant decrease in activity was observed after the administration of 5 mg/kg. The effect of
U-47,476A on locomotor activity in the mouse was significantly less than that for an approximately equipotent
analgesic dose of
clonidine. The
analgesic effect of
U-47,476A was antagonized by
yohimbine, but not by
reserpine,
naloxone or
phentolamine, Thus, the attenuation of the response to noxious stimuli by
U-47,476A is mediated by alpha 2-adrenoceptors and not by
opioid receptors or presynaptic monoaminergic mechanisms, similar to
clonidine-induced
analgesia.