Antinociceptive action of McN-5195 in rodents: a structurally novel (indolizine) analgesic with a nonopioid mechanism of action

JL Vaught, JR Carson, RJ Carmosin, PS Blum, FJ Persico, WE Hageman, RP Shank and RB Raffa

Department of Biological, Research, McNeil Pharmaceutical, Spring House, Pennsylvania.

McN-5195 [(+/-)-trans-3-(2-bromophenyl)-octahydroindolizine] inhibited at nontoxic doses the nociceptive response in tail-pinch, tail-flick and 48 degrees C hot-plate tests of mice, with ED50 values of 38.2, 33.9 and 30.9 mg/kg i.p., respectively, and of rats, with ED50 values (i.p.) of 33.2 mg/kg (tail-flick) and 33.3 mg/kg (hot-plate). The compound was p.o. active in the acetylcholine-induced irritant test (ED50 = 20.1 mg/kg) in mice and the air-induced irritant test (ED50 = 33.2 mg/kg) in rats. McN-5195 blocked thalamic activity (multiunit recordings from the ventral posterolateral nucleus) evoked by noxious stimulation of the contralateral hindlimb of anesthetized rats, but did not alter thalamic activity during non-noxious stimulation. The antinociceptive action of McN-5195 was not blocked by naloxone and was not diminished in morphine-tolerant animals. McN-5195 did not affect arachidonate metabolism and was not active against carrageenan-induced paw edema or in an adjuvant arthritis test in rats. McN-5195 did not bind to opiate, serotonin S1 or S2, dopamine D2, alpha-1, alpha-2, beta adrenergic or gamma-aminobutyric acid-A receptors and did not inhibit the synaptic uptake of norepinephrine, serotonin, dopamine or gamma- aminobutyric acid. McN-5195-induced antinociception was not affected by reserpine or phentolamine pretreatment and was not reduced in clonidine- tolerant animals. Ketanserin and yohimbine inhibited McN-5195-induced antinociception by an indirect mechanism. Tolerance did not develop to chronic administration of McN-5195 (120 mg/kg 3 times per day for 10 days). We conclude that McN-5195 is a structurally novel (indolizine) antinociceptive agent that produces its analgesic action via a nonopioid mechanism, not involving products of arachidonate metabolism.

Volume 255, Issue 1, pp. 1-10, 10/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics