title: A new class of potent centrally acting muscle relaxants: pharmacology of oxazolidinones in rat decerebrate rigidity.
abstract: 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.
mesh_terms: 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
chemical_list: 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