Pharmacological properties and mechanism of action of the cyclopyrrolones.
We present the pharmacological properties of two cyclopyrrolones, zopiclone as a hypnotic and suriclone as an anxiolytic, and examine their mechanism of action. The effects of zopiclone on the amount of time spent at each vigilance level have been studied in freely moving rats. Zopiclone from 2.5 mg/kg i.p. extends the duration of slow wave sleep (SWS), concomitantly shortening the periods awake. This SWS inducing effect of zopiclone was more potent after 10 mg/kg i.p.; moreover, zopiclone did not depress REM sleep and no rebound of activity in wakefulness or REM sleep were observed the day after zopiclone treatment. In rats, at the cortical level, zopiclone increases the spectral energy in the delta band (0.5 to 4 hertz). This rise in energy appears at doses starting from 1.25 mg/kg p.o. and can also reach the fast frequencies (beta band: 12 to 16 hertz). This power spectrum is characteristic of a compound having tranquilizing-hypnotic potential. Taken together these EEG results corroborate the clinical studies. In man, zopiclone increased SWS, decreased SWS latency and respected sleep architecture in both healthy volunteers and insomniacs. This respect of sleep structure and the relative short duration of action of zopiclone minimized the residual effects seen upon waking (drowsiness, impairment of psychomotor performance). In the Geller-Seifter test, an operant conflict procedure, the minimal effective dose (MED) of suriclone in reversing the conflict-induced inhibition of drinking behavior was 2.5 mg.kg-1 p.o. in rats. Depression of unpunished responding is only seen at higher doses (20 mg.kg-1 p.o.).(ABSTRACT TRUNCATED AT 250 WORDS)
Biology Department, Rhone Poulenc Rorer, Vitry-sur-Seine.
J M
JM
Stutzmann
O
O
Piot
M
M
Reibaud
A
A
Doble
J C
JC
Blanchard
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy; D053961:Azabicyclo Compounds; D004569:Electroencephalography; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009287:Naphthyridines; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011963:Receptors, GABA-A / Q000187:drug effects; D012890:Sleep / Q000187:drug effects; D013457:Sulfur Compounds
D014151:Anti-Anxiety Agents; D053961:Azabicyclo Compounds; D006993:Hypnotics and Sedatives; D009287:Naphthyridines; D010879:Piperazines; D011963:Receptors, GABA-A; D013457:Sulfur Compounds; C515050:zopiclone; C037283:suriclone