Stimulation of brain steroidogenesis by 2-aryl-indole-3-acetamide derivatives acting at the mitochondrial diazepam-binding inhibitor receptor complex.
The 2-aryl-indole-3-acetamide derivatives, 2-hexyl-indole-3-acetamide (FGIN-1-27) and 2-hexyl-indole-3-acetamide-N-benzene-tricarboxylic acid (FGIN-1-44) displaced [3H]1-(2-chlorophenyl)-N-methyl-N-(1- methylpropyl)-3-isoquinoline-carboxamide([3H]PK 11195) and [3H]4-chlorodiazepam ([3H]4'CD) from binding sites located on the rat brain mitochondrial DBI receptor complex (MDRC) with Ki values in the nanomolar range. Both 2-aryl-indole-3-acetamide derivatives acted as agonists at the MDRC and thereby stimulated the rate of pregnenolone synthesis in isolated rat brain mitochondria; this effect was inhibited by PK 11195, an MDRC ligand that does not possess steroidogenic activity. FGIN-1-27 and FGIN-1-44 failed to bind to other transmitter receptors, including gamma-aminobutyric-A receptors. When administered orally to rats, both FGIN-1-27 and FGIN-1-44 reduced fear of novelty in the elevated plus maze test. This action was prevented by PK 11195, but not by flumazenil. FGIN-1-44, which was rapidly converted to FGIN-1-27 in the rat brain, was 3 to 4 times more potent than FGIN-1-27 in reducing fear of novelty because of its greater bioavailability. FGIN-1-27 increased the brain pregnenolone content in adrenalectomized-castrated rats pretreated with trilostane (in order to prevent metabolism of pregnenolone to progesterone). This increase was blocked by pretreatment with PK 11195. Although FGIN-1-27 and FGIN-1-44 increased the corticosterone concentration in adrenal glands and plasma of hypophysectomized rats in a PK 11195-sensitive manner, both drugs failed to increase adrenal steroidogenesis in sham-operated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Romeo
E
E
Fidia-Georgetown Institute for the Neurosciences, Washington, District of Columbia.
Cavallaro
S
S
Korneyev
A
A
Kozikowski
A P
AP
Ma
D
D
Polo
A
A
Costa
E
E
Guidotti
A
A
D000311:Adrenal Glands / Q000378:metabolism; D000315:Adrenalectomy; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001570:Benzodiazepinones / Q000378:metabolism; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D003345:Corticosterone / Q000378:metabolism; D026261:Diazepam Binding Inhibitor; D066298:In Vitro Techniques; D007210:Indoleacetic Acids / Q000494:pharmacology*; D007546:Isoquinolines / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009919:Orchiectomy; D011284:Pregnenolone / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013256:Steroids / Q000096:biosynthesis*; D014233:Tricarboxylic Acids / Q000494:pharmacology*
D001570:Benzodiazepinones; D002352:Carrier Proteins; D026261:Diazepam Binding Inhibitor; D007210:Indoleacetic Acids; D007546:Isoquinolines; D013256:Steroids; D014233:Tricarboxylic Acids; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; C083895:2-hexylindole-3-acetamide-N-benzenetricarboxylic acid; C028513:4'-chlorodiazepam; D011284:Pregnenolone; D003345:Corticosterone; C037850:PK 11195