The antinociceptive effects and pharmacological properties of JM-1232(-): a novel isoindoline derivative.
BACKGROUND
An isoindoline derivative, JM-1232(-) was developed as a sedative and analgesic drug. We performed the present study to investigate its antinociceptive effects on three different nociceptions in mice.


METHODS
Mail ddY mice were administered intraperitoneal (i.p.) JM-1232(-) 1,3 or 10 mg/kg (n = 8 for each dose in each test). Saline was used as a control. The hotplate or tail pressure test was performed for 120 min after i.p. drug injection. Acetic acid 0.6% solution in 10 mL/kg was i.p. administered 15 min after i.p. drug injection in the acetic acid test. The number of abdominal constriction episodes was counted for 10 min, starting 5 min after i.p. administration of the acid. When the analgesic effect was observed, naloxone or flumazenil was subcutaneously administered before administration of the maximum effective dose of JM-1232(-). Using the wheel running test, the number of wheel revolutions was recorded every 5 min for 120 min.


RESULTS
In the hotplate, tail pressure and acetic acid tests, i.p. JM-1232(-) produced significant antinociceptive effects with a 50% effective dose of 2.96 mg/kg (CI: 2.65-3.30 mg/kg), 3.06 mg/kg (CI: 2.69-3.47 mg/kg) and 2.27 mg/kg (CI: 1.46-3.53 mg/kg), respectively. In all tests, JM-1232(-)-induced antinociception was antagonized by flumazenil (5 mg/kg) but not by naloxone (10 mg/kg). In the running wheel test, there was no dose-dependent effect of JM-1232(-) on locomotor activity.


CONCLUSIONS
Systemically administered JM-1232(-) had antinociceptive effects on acute thermal, mechanical-induced pain, and visceral pain in mice. These effects might be mediated by benzodiazepine-gamma-aminobutyric acid type A receptors but not by opioid receptors.
Chiba
Shunsuke
S
Department of Anesthesiology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan. chiba@bb.e-mansion.com
Nishiyama
Tomoki
T
Yamada
Yoshitsugu
Y
D019342:Acetic Acid; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006358:Hot Temperature; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D054833:Isoindoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D010879:Piperazines / Q000494:pharmacology*; D011312:Pressure; D011930:Reaction Time
C534223:3-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-2-phenyl-3,5,6,7-tetrahydrocyclopenta(f)isoindol-1(2H)-one; D000700:Analgesics; D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D054833:Isoindoles; D009292:Narcotic Antagonists; D010879:Piperazines; D009270:Naloxone; D005442:Flumazenil; D019342:Acetic Acid