RT Journal Article
SR Electronic
T1 Antagonism of gamma-aminobutyric acidA receptor-mediated responses by amino-gamma-carbolines.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1269
OP 1276
VO 252
IS 3
A1 Y Kanai
A1 O Wada
A1 S Manabe
YR 1990
UL http://jpet.aspetjournals.org/content/252/3/1269.abstract
AB The amino-gamma-carbolines 3-amino-1-methyl-5H-pyrido[4,3-b]indole and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole were demonstrated to be potent convulsants. Administered i.p. in rats, these compounds penetrated the blood-brain barrier rapidly and appeared in the cerebrospinal fluid. When administered i.c.v., they induced convulsions with short onset latencies, suggesting that these compounds themselves have convulsant activities. In in vitro experiments using the whole cell clamp method, they suppressed gamma-aminobutyric acid (GABA)-induced Cl- current isolated on the dissociated mouse sensory neurons in dose-dependent manners through their actions as antagonists at GABAA receptors. The relative potency of the suppressive effects on GABA-induced Cl- current was compatible with that of the convulsant activities in mice. Furthermore, Ro15-1788 did not affect their convulsant activities. These results suggested that the amino-gamma-carbolines induced convulsions through their actions as antagonists at GABAA receptors and not through their actions as inverse agonists or antagonists at benzodiazepine receptors. Structure-activity relationships indicated that the 3-amino-group is important for the activities of amino-gamma-carbolines as GABAA receptor antagonists.