2-Aryl-3-indoleacetamides (FGIN-1): a new class of potent and specific ligands for the mitochondrial DBI receptor (MDR).

Abstract

The 2 aryl-3-indoleacetamides (FGIN-1) are a new class of compounds that potently (nM) and selectively bind to glial mitochondrial diazepam binding inhibitor (DBI) receptors (MDR), previously called peripheral benzodiazepine receptors, and increase mitochondrial steroidogenesis. The high-affinity binding of FGIN-1 to MDR derivatives depends on the following chemical characteristics: 1) the dialkylation of the amide; 2) the chain length of this alkyl substitution; and 3) the halogenation of aryl groups appended to the indole nucleus. FGIN-1 derivatives do not bind to gamma-aminobutyric acid (GABAA), GABAB, glycine, glutamate, dopamine, serotonin, opiate, cholecystokinin, beta adrenergic, cannabinoid or sigma receptors. FGIN-1-27 [N, N-di-n-hexyl 2-(4-fluorophenyl)indole-3-acetamide] enters the brain, and for this reason, this FGIN-1 compound is potent and efficacious behaviorally. Like the neurosteroid 3 alpha-5 alpha tetrahydrodeoxycorticosterone (THDOC), FGIN-1-27 delays the onset of isoniazid-induced convulsions, but fails to delay the onset of bicuculline-induced convulsions. However, differently from THDOC, the FGIN-1-27 anticonvulsant action is blocked by the isoquinoline carboxamide PK 11195. In the elevated plus maze test, FGIN-1-27 inhibits neophobia manner that is antagonized by PK 11195 but not by flumazenil. Because FGIN-1-27 binds to MDR and does not bind to the GABAA receptors, it is inferred that FGIN-1-27 may act on GABAA receptors indirectly, presumably via a stimulation of neurosteroid synthesis and release from glial cells.

• Authors: E Romeo, J Auta, A P Kozikowski, D Ma, V Papadopoulos, G Puia, E Costa, A Guidotti
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 262 Issue 3 Pg. 971-8 (Sep 1992) ISSN: 0022-3565 [Print] United States
• PMID: 1326631 (Publication Type: Journal Article)

Chemical References

• Acetamides
• Diazepam Binding Inhibitor
• Indoleacetic Acids
• Ligands
• Neuropeptides
• Receptors, GABA-A
• Pregnenolone
• Isoniazid
• Bicuculline

Topics

• Acetamides (chemical synthesis, metabolism, pharmacology)
• Animals
• Bicuculline (toxicity)
• Binding, Competitive
• Brain (drug effects, metabolism)
• Diazepam Binding Inhibitor
• Indoleacetic Acids (chemical synthesis, metabolism, pharmacology)
• Isoniazid (antagonists & inhibitors, toxicity)
• Ligands
• Mitochondria (drug effects, metabolism)
• Motor Activity (drug effects)
• Neuropeptides (metabolism)
• Pregnenolone (biosynthesis)
• Rats
• Rats, Inbred Strains
• Receptors, GABA-A (drug effects, metabolism)
• Seizures (chemically induced)