Participation of mitochondrial diazepam binding inhibitor receptors in the anticonflict, antineophobic and anticonvulsant action of 2-aryl-3-indoleacetamide and imidazopyridine derivatives.
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 gamma-aminobutyric acidA receptor where the benzodiazepines bind. FGIN-1-27 and alpidem, like the neurosteroid 3 alpha,21-dehydroxy-5 alpha-pregnane-20-one (THDOC), clonazepam and zolpidem (the direct allosteric modulators of gamma-aminobutyric acidA 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Auta
J
J
Fidia-Georgetown Institute for the Neurosciences, Washington, District of Columbia.
Romeo
E
E
Kozikowski
A
A
Ma
D
D
Costa
E
E
Guidotti
A
A
D000374:Aggression; D000494:Allosteric Regulation; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002998:Clonazepam / Q000378:metabolism / Q000494:pharmacology; D003900:Desoxycorticosterone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D007210:Indoleacetic Acids / Q000494:pharmacology*; D007538:Isoniazid / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism*; D010698:Phobic Disorders; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear; D011963:Receptors, GABA-A / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced; D000077334:Zolpidem
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D007093:Imidazoles; D007210:Indoleacetic Acids; D007546:Isoquinolines; D011725:Pyridines; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D011963:Receptors, GABA-A; C078199:diazepam-binding inhibitor receptor; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; D003900:Desoxycorticosterone; D005442:Flumazenil; C009413:tetrahydrodeoxycorticosterone; D002998:Clonazepam; D000077334:Zolpidem; C052036:alpidem; D007538:Isoniazid; C037850:PK 11195