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

The effect of several pyrolysate mutagens on the benzodiazepine and GABA receptors was investigated. Of amino-gamma-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 Kd, indicating that these gamma-carbolines bind on benzodiazepine and GABA receptors. IC50S 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 gamma-carbolines may be mediated by an action on the central benzodiazepine receptors; however, the role of the effect on GABA receptors is not clear.