Gabuculine and isogabaculine: in vivo biochemistry and pharmacology in mice.

Two irreversible enzyme-activated GABA-transaminase inhibitors, gabaculine (5-amino cyclohex-1, 3-dienyl carboxylic acid) and an isomer, isogabaculine (3-amino cyclohex-1, 5-dienyl carboxylic acid), were investigated in mice for their effects on brain GABA metabolism and on seizures induced by a variety of stimuli. Biochemical and pharmacological activities of the two inhibitors were very similar. Both produce dose- and time-related, sustained inhibition of GABA-T activity and, to a lesser extent, of GAD activity and long-lasting increases in brain GABA concentrations. Both protect mice against audiogenic seizures and significantly decrease the frequency of seizures induced by isoniazid, thiosemicarbazide and pentylenetetrazol. They do not affect the frequency of seizures induced by strychnine, bicuculline or picrotoxin and do not alter the threshold to electroconvulsive shock. Although the effects of gabaculine and isogabaculine on brain GABA metabolism resemble those of other GABA-T inhibitors, important differences in pharmacological activities exist.