5-(2-Cyclohexylideneethyl)-5-ethyl barbituric acid (CHEB): correlation of hypnotic and convulsant properties with alterations of synaptosomal 45Ca2+ influx.
Male ICR mice (20-35 g) were given either 5-(2-cyclohexylideneethyl)-5-ethyl barbituric acid (CHEB) alone (10-15 mg/kg i.p.) or CHEB (25-75 mg/kg i.p.) after a 1 h pretreatment with phenobarbital (75 mg/kg i.p.). CHEB alone (10 mg/kg) produced excitatory behavior but not convulsive seizures. Higher doses (11-15 mg/kg) produced convulsive seizures resulting in death. Pretreatment with phenobarbital prevented seizure activity. Following phenobarbital pretreatment, CHEB in doses of 50 and 75, but not 25 mg/kg, resulted in hypnosis of 53 +/- 16 and 64 +/- 9 min duration, respectively. In vitro, CHEB (10-200 microM) significantly inhibited 'fast-phase' (3 s) K+-stimulated 45Ca2+ uptake into cerebrocortical synaptosomes. CHEB (10 and 100 microM) also significantly increased basal 45Ca2+ uptake. The addition of CHEB (50 and 100 microM) or pentobarbital (100 microM) to striatal synaptosomes inhibited 'fast-phase' K+-stimulated 45Ca2+ uptake and endogenous dopamine release. CHEB (10-200 microM), but not pentobarbital (100 microM), produced a time- and dose-dependent increase in the resting release of endogenous dopamine from striatal synaptosomes. The results of this study show that CHEB possesses hypnotic activity if its lethal convulsant actions are blocked. The hypnotic actions of CHEB appear to correlate with inhibition of voltage-dependent calcium channels in brain synaptosomes.
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001463:Barbiturates / Q000031:analogs & derivatives / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002132:Calcium Radioisotopes; D003292:Convulsants; D004298:Dopamine / Q000378:metabolism; D006993:Hypnotics and Sedatives; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D000927:Anticonvulsants; D001463:Barbiturates; D002132:Calcium Radioisotopes; D003292:Convulsants; D006993:Hypnotics and Sedatives; C024321:5-(2-cyclohexylidene-ethyl)-5-ethylbarbiturate; D002118:Calcium; D004298:Dopamine; D010634:Phenobarbital