Inhibition of benzodiazepine and GABA receptor binding by amino-γ-carbolines and other amino acid pyrolysate mutagens

Abstract

The effect of several pyrolysate mutagens on the benzodiazepine and GABA receptors was investigated. Of amino-γ-carbolines, Trp-P-1 antagonized the suppressive effect of diazepam on the pentylenetetrazol-induced convulsions and death, whereas Trp-P-2 by itself precipitated seizures and death in male mice. Both Trp-P-1 and Trp-P-2 inhibited the specific binding of [ 3H]diazepam and [ 3H]muscimol in rat brain membranes mainly by increasing K d, indicating that these γ-carbolines bind on benzodiazepine and GABA receptors. IC 50s of Trp-P-1 and Trp-P-2 on specific [ 3H]flunitrazepam binding were not changed by addition of GABA. The Hill coefficient of Trp-P-1 for displacing [ 3H]diazepam binding was about unity whereas that of Trp-P-2 was less than unity. These results suggest that Trp-P-1 and Trp-P-2 act as active antagonists or inverse agonists at benzodiazepine receptors. The convulsant effect of the γ-carbolines may be mediated by an action on the central benzodiazepine receptors; however, the role of the effect on GABA receptors is not clear.