The analgesic activity of a clonidine analog. The formamidine, U-47,476A.

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.