Stimulation of brain steroidogenesis by 2-aryl-indole-3-acetamide derivatives acting at the mitochondrial diazepam-binding inhibitor receptor complex
Romeo, E.; Cavallaro, S.; Korneyev, A.; Kozikowski, A.P.; Ma, D.; Polo, A.; Costa, E.; Guidotti, A.
Journal of Pharmacology and Experimental Therapeutics 267(1): 462-471
1993
ISSN/ISBN: 0022-3565 PMID: 8229777 Document Number: 412249
The 2-aryl-indole-3-acetamide derivatives, 2-hexyl-indole-3-acetamide (FGIN-1-27) and 2-hexyl-indole-3-acetamide-N-benzenetricarboxylic 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 K-i 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 PK11195, 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-144 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. Because the PK 11195-sensitive antineophobic action of FGIN-1 derivatives was also apparent in adrenalectomized-castrated rats, we conclude that neurosteroids produced as a result of brain MDRC stimulation may contribute to the pharmacological actions of these drugs.