A new class of potent centrally acting muscle relaxants: pharmacology of oxazolidinones in rat decerebrate rigidity.
The severity of anaemic decerebrate rigidity was quantitatively determined by measuring the frequency of electromyographic potentials in the rat. Some oxazolidinones markedly reduced the severity of this decerebrate rigidity in a dose-dependent manner, (4S,5R)-4-(2-methylpropyl)-3- [3-(perhydroazepin-1-yl)propyl]-5-phenyl-1,3-oxazolidin-2-on e (MLV-6976) being the most potent. In addition to the oxazolidinones, an aminoalcohol derivative, (1RS,2SR)-5-methyl-1-phenyl-2-(3-piperidinopropylamino )hexan-1-ol (MLV-5860) also reduced the rat decerebrate rigidity. In the oxazolidinone series, the optical isomers with absolute configuration (S) at the 4-position were more potent than the corresponding (4R)-isomers, while there was no significant difference in their LD50 values. Normal rats and mice receiving MLV-6976 at doses which reduced decerebrate rigidity showed no behavioural changes, impairment of motor coordination only appearing at extremely high doses. MLV-6976 and its derivatives did not affect spinal reflex potentials in cats. MLV-6976 reduced the severity of harmaline-induced tremor in mice in a dose-dependent manner, but slightly augmented tremorine-induced tremor. The frequency of the spike discharges induced by iontophoretically applied glutamate was reduced by MLV-6976 in a dose-dependent manner in rat cortical neurones. The amplitude of miniature endplate potentials of the rat diaphragm was decreased by MLV-6976 only at concentrations greater than 0.1 mM. It is concluded that MLV-6976 acts on the brainstem or/and higher levels of the brain rather than on the spinal cord or the peripheral nervous system to reduce the excessive activities of the nervous system.
D000818:Animals; D001381:Azepines; D003655:Decerebrate State; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D008297:Male; D009045:Motor Endplate / Q000187:drug effects; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D009127:Muscle Rigidity / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects; D010080:Oxazoles / Q000494:pharmacology*; D023303:Oxazolidinones; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012018:Reflex / Q000187:drug effects; D014202:Tremor / Q000517:prevention & control
D001381:Azepines; D018691:Excitatory Amino Acid Antagonists; D009125:Muscle Relaxants, Central; D010080:Oxazoles; D023303:Oxazolidinones; D010880:Piperidines; C048986:MLV 5860; C051400:MLV 6976; C051401:MLV 3076; D018698:Glutamic Acid