The
analgesic and acute central nervous system (CNS) side effect potential of the
enkephalinase inhibitor
SCH 32615 (N-[L-(1-carboxy-2-phenyl)ethyl]-L-phenyl-
alanine-
beta-alanine) were evaluated after IV administration to mice, rats and squirrel monkeys. In mice,
SCH 32615 caused dose-related suppression of
acetic acid-induced writhing (minimal effective dose, MED = 3 mg/kg IV). In rats,
SCH 32615 produced dose-related increases in the response latencies in the yeast inflamed-paw test (MED = 10 mg/kg IV). In squirrel monkeys, using a new hot-water bath tail-flick test,
SCH 32615 significantly prolonged the escape latencies (MED = 100 mg/kg IV). These results in primates are the first data showing an
analgesic action of an
enkephalinase inhibitor in a reflex model of
pain. When measured for its CNS side effect potential,
SCH 32615 had no significant effects in rats (up to 100 times its analgesically active doses) or in monkeys (up to three times). In the mouse, at doses 100 times its minimal effective dose,
SCH 32615 produced brief convulsions; these lasted only a minute, resolved quickly, and did not cause lethality. In contrast, in rats and squirrel monkeys, the standard
opioid analgesic morphine produced profound CNS side effects; this was particularly notable in monkeys, in which
morphine's maximal
analgesic effects were associated with near lethal
respiratory depression. These data demonstrate that
SCH 32615 produces selective
analgesic actions and that its acute side effect liability is less than that seen with a clinically used standard.