Antinociceptive action of McN-5195 in rodents: a structurally novel (indolizine) analgesic with a nonopioid mechanism of action.
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.
Vaught
J L
JL
Department of Biological, Research, McNeil Pharmaceutical, Spring House, Pennsylvania.
Carson
J R
JR
Carmosin
R J
RJ
Blum
P S
PS
Persico
F J
FJ
Hageman
W E
WE
Shank
R P
RP
Raffa
R B
RB
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007212:Indolizines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D011957:Receptors, Opioid / Q000187:drug effects; D013788:Thalamus / Q000187:drug effects / Q000502:physiology
D000700:Analgesics; D001095:Arachidonic Acids; D007212:Indolizines; D011942:Receptors, Adrenergic, alpha; D011957:Receptors, Opioid; C058653:3-(2-bromophenyl)octahydroindolizine; D016718:Arachidonic Acid