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.
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology*; D002712:Chlorides / Q000378:metabolism; D003975:Diazepam / Q000378:metabolism; D005445:Flunitrazepam / Q000378:metabolism; D006247:Harmine / Q000031:analogs & derivatives / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007473:Ion Channels / Q000187:drug effects; D007700:Kinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009118:Muscimol / Q000378:metabolism; D009153:Mutagens / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011963:Receptors, GABA-A; D012640:Seizures / Q000139:chemically induced
D002243:Carbolines; D002712:Chlorides; D007211:Indoles; D007473:Ion Channels; D009153:Mutagens; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D009118:Muscimol; D006247:Harmine; D005445:Flunitrazepam; C019133:3-amino-1-methyl-5H-pyrido(4,3-b)indole; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole; D003975:Diazepam