Analgesic and acute central nervous system side effects of the intravenously administered enkephalinase inhibitor SCH 32615.
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.
Chipkin
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Schering-Plough Research, Bloomfield, NJ 07003.
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D000085:Acetates; D019342:Acetic Acid; D000700:Analgesics; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects*; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000503:physiopathology; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time / Q000187:drug effects; D012453:Saimiri
D000085:Acetates; D000700:Analgesics; D004151:Dipeptides; D009020:Morphine; C062344:SCH 32615; D015260:Neprilysin; D019342:Acetic Acid