Participation of mitochondrial diazepam binding inhibitor receptors in the anticonflict, antineophobic and anticonvulsant action of 2-aryl-3- indoleacetamide and imidazopyridine derivatives

J. Auta, E. Romeo, A. Kozikowski, D. Ma, E. Costa, A. Guidotti

Research output: Contribution to journalArticle

Abstract

The 2-hexyl-indoleacetamide derivative, FGIN-1-27 [N,N-di-n-hexyl-2-(4- fluorophenyl)indole-3-acetamide], and the imidazopyridine derivative, alpidem, both bind with high affinity to glial mitochondrial diazepam binding inhibitor receptors (MDR) and increase mitochondrial steroidogenesis. Although FGIN-1-27 is selective for the MDR, alpidem also binds to the allosteric modulatory site of the γ-aminobutyric acid(A) receptor where the benzodiazepines bind. FGIN-1-27 and alpidem, like the neurosteroid 3α,21- dehydroxy-5α-pregnane-20-one (THDOC), clonazepam and zolpidem (the direct allosteric modulators of γ-aminobutyric acid(A) receptors) delay the onset of isoniazid and metrazol-induced convulsions. The anti-isoniazid convulsant action of FGIN-1-27 and alpidem, but not that of THDOC, is blocked by PK 11195. In contrast, flumazenil blocked completely the anticonvulsant action of clonazepam and zolpidem and partially blocked that of alpidem, but it did not affect the anticonvulsant action of THDOC and FGIN-1-27. Alpidem, like clonazepam, zolpidem and diazepam, but not THDOC or FGIN-1-27, delay the onset of bicuculline-induced convulsions. In two animal models of anxiety, the neophobic behavior in the elevated plus maze test and the conflict- punishment behavior in the Vogel conflict test, THDOC and FGIN-1-27 elicited anxiolytic-like effects in a manner that is flumazenil insensitive, whereas alpidem elicited a similar anxiolytic effect, but is partially blocked by flumazenil. Whereas PK 11195 blocked the effect of FGIN-1-27 and partially blocked alpidem, it did not affect THDOC in both animal models of anxiety. Because both alpidem and FGIN-1-27 bind to MDR and stimulate mitochondrial steroid biosynthesis, the behavioral effects of FGIN-1-27 and in part alpidem may be mediated via MDR-induced steroidogenesis.

Original languageEnglish (US)
Pages (from-to)649-656
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume265
Issue number2
StatePublished - 1993
Externally publishedYes

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Anticonvulsants
Clonazepam
Flumazenil
Aminobutyrates
Anti-Anxiety Agents
Isoniazid
Seizures
N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide
diazepam-binding inhibitor receptor
indoleacetamide
Anxiety
Animal Models
alpidem
Allosteric Site
Convulsants
Pentylenetetrazole
Punishment
Bicuculline
GABA-A Receptors
Diazepam

ASJC Scopus subject areas

  • Pharmacology

Cite this

Participation of mitochondrial diazepam binding inhibitor receptors in the anticonflict, antineophobic and anticonvulsant action of 2-aryl-3- indoleacetamide and imidazopyridine derivatives. / Auta, J.; Romeo, E.; Kozikowski, A.; Ma, D.; Costa, E.; Guidotti, A.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 265, No. 2, 1993, p. 649-656.

Research output: Contribution to journalArticle

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abstract = "The 2-hexyl-indoleacetamide derivative, FGIN-1-27 [N,N-di-n-hexyl-2-(4- fluorophenyl)indole-3-acetamide], and the imidazopyridine derivative, alpidem, both bind with high affinity to glial mitochondrial diazepam binding inhibitor receptors (MDR) and increase mitochondrial steroidogenesis. Although FGIN-1-27 is selective for the MDR, alpidem also binds to the allosteric modulatory site of the γ-aminobutyric acid(A) receptor where the benzodiazepines bind. FGIN-1-27 and alpidem, like the neurosteroid 3α,21- dehydroxy-5α-pregnane-20-one (THDOC), clonazepam and zolpidem (the direct allosteric modulators of γ-aminobutyric acid(A) receptors) delay the onset of isoniazid and metrazol-induced convulsions. The anti-isoniazid convulsant action of FGIN-1-27 and alpidem, but not that of THDOC, is blocked by PK 11195. In contrast, flumazenil blocked completely the anticonvulsant action of clonazepam and zolpidem and partially blocked that of alpidem, but it did not affect the anticonvulsant action of THDOC and FGIN-1-27. Alpidem, like clonazepam, zolpidem and diazepam, but not THDOC or FGIN-1-27, delay the onset of bicuculline-induced convulsions. In two animal models of anxiety, the neophobic behavior in the elevated plus maze test and the conflict- punishment behavior in the Vogel conflict test, THDOC and FGIN-1-27 elicited anxiolytic-like effects in a manner that is flumazenil insensitive, whereas alpidem elicited a similar anxiolytic effect, but is partially blocked by flumazenil. Whereas PK 11195 blocked the effect of FGIN-1-27 and partially blocked alpidem, it did not affect THDOC in both animal models of anxiety. Because both alpidem and FGIN-1-27 bind to MDR and stimulate mitochondrial steroid biosynthesis, the behavioral effects of FGIN-1-27 and in part alpidem may be mediated via MDR-induced steroidogenesis.",
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