8229777

pubmed:Citation

1

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)

eng

IM

MEDLINE

0022-3565

Print

NLM

462-71

pubmed-meshheading:8229777-Adrenal Glands, pubmed-meshheading:8229777-Adrenalectomy, pubmed-meshheading:8229777-Animals, pubmed-meshheading:8229777-Behavior, Animal, pubmed-meshheading:8229777-Benzodiazepinones, pubmed-meshheading:8229777-Binding, Competitive, pubmed-meshheading:8229777-Brain, pubmed-meshheading:8229777-Carrier Proteins, pubmed-meshheading:8229777-Corticosterone, pubmed-meshheading:8229777-Diazepam Binding Inhibitor, pubmed-meshheading:8229777-Indoleacetic Acids, pubmed-meshheading:8229777-Isoquinolines, pubmed-meshheading:8229777-Male, pubmed-meshheading:8229777-Mitochondria, pubmed-meshheading:8229777-Orchiectomy, pubmed-meshheading:8229777-Pregnenolone, pubmed-meshheading:8229777-Rats, pubmed-meshheading:8229777-Rats, Sprague-Dawley, pubmed-meshheading:8229777-Solubility, pubmed-meshheading:8229777-Steroids, pubmed-meshheading:8229777-Tricarboxylic Acids

Stimulation of brain steroidogenesis by 2-aryl-indole-3-acetamide derivatives acting at the mitochondrial diazepam-binding inhibitor receptor complex.

Journal Article, In Vitro, Research Support, U.S. Gov't, P.H.S.