Studies on the muscle relaxation effects of ethyl loflazepate (CM6912) and evaluation as an anti-anxiety drug.
A new anti-anxiety drug, CM6912 (ethyl loflazepate, ethyl 7-chloro-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepine-3- carboxylate), was investigated for its effects on the alpha- and gamma-motor systems and on the cooperative muscular motions and for its interactions with other CNS drugs. The results obtained are as follows: Muscular discharges (EMG) induced by decerebrate rigidity were unaffected by 10 mg/kg (p.o.) of CM6912, but the amplitudes of the EMG were reduced by 50% for 3 hr by 30 mg/kg of CM6912 at 30 min after administration. Diazepam (10 mg/kg) also decreased the amplitudes of the EMG even at 5 min after administration, indicating that diazepam had a stronger than CM6912. Both monosynaptic spinal reflex (MSR) and polysynaptic spinal reflex (PSR) were unaffected by CM6912 (100 mg/kg). Dorsal root reflex potential was slightly enhanced by CM6912 (100 mg/kg), but not at a dose of 30 mg/kg. Diazepam (10 mg/kg) did not decrease MSR, but slightly reduced PSR. Dorsal root reflex potential was almost doubled by diazepam. The frequency of spontaneous discharges of Gla spindle afferent fiber of the extensor muscle of the hindlimb of anesthetized cats was unchanged by 10 mg/kg CM6912, but was suppressed by diazepam at the same dose while at a dose of 30 mg/kg, it was reduced mildly by CM6912, and markedly by diazepam. ED50 values for the antagonistic action on bemegride-induced convulsions were 0.30 mg/kg for CM6912 and 0.49 mg/kg for diazepam at 1 hr after administration, and they were 0.30 mg/kg and 0.67 mg/kg for CM6912 and diazepam, respectively, at 4 hr. The potentiating action of CM6912 on chlorprothixene-induced anesthesia was far weaker than that of diazepam. The suppressive potency of CM6912 on the adaptability to the rotarod was about half that of diazepam, and the muscle relaxant action of CM6912, examined by the inclined board test and the hanging test, was found to be similar to that of diazepam. These results suggest that CM6912 is less potent than diazepam in reducing muscular tone and in inducing sleep, while it has a stronger and longer-lasting anti-anxietic activity than diazepam.
D000223:Adaptation, Psychological / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001534:Bemegride / Q000494:pharmacology; D001569:Benzodiazepines; D001570:Benzodiazepinones / Q000494:pharmacology*; D002415:Cats; D003655:Decerebrate State; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D009127:Muscle Rigidity / Q000188:drug therapy; D009132:Muscles / Q000187:drug effects*; D004856:Postural Balance / Q000187:drug effects; D012018:Reflex / Q000187:drug effects
D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D001569:Benzodiazepines; D001534:Bemegride; C029617:ethyl loflazepate