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

E. Romeo, J. Auta, A. P. Kozikowski, D. Ma, V. Papadopoulos, G. Puia, E. Costa, A. Guidotti

Research output: Contribution to journalArticle

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 γ-aminobutyric acid (GABA(A)), GABA(B), 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 3α-5α 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 in a manner that is antagonized by PK 11195 but not by flumazenil. Because FGIN-1-27 binds to MDR and does not bind to the GABA(A) receptors, it is inferred that FGIN-1-27 may act on GABA(A) receptors indirectly, presumably via a stimulation of neurosteroid synthesis and release from glial cells.

Original languageEnglish (US)
Pages (from-to)971-978
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume262
Issue number3
StatePublished - Jan 1 1992

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Romeo, E., Auta, J., Kozikowski, A. P., Ma, D., Papadopoulos, V., Puia, G., Costa, E., & Guidotti, A. (1992). 2-Aryl-3-indoleacetamides (FGIN-1): A new class of potent and specific ligands for the mitochondrial DBI receptor (MDR). Journal of Pharmacology and Experimental Therapeutics, 262(3), 971-978.