Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P07108 (diazepam binding inhibitor)
 460 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:2-Aryl-3-indoleacetamides (FGIN-1): a new class of potent and specific ligands for the mitochondrial DBI receptor (MDR). 132 31

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)
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PMID:Participation of mitochondrial diazepam binding inhibitor receptors in the anticonflict, antineophobic and anticonvulsant action of 2-aryl-3-indoleacetamide and imidazopyridine derivatives. 809 60

Evidence that neurosteroids are potent modulators of the action of GABA at GABAA receptors has prompted the investigation of the mechanism that controls brain neurosteroid synthesis by glial cell mitochondria in vivo. In vitro studies suggest that the interaction of the diazepam binding inhibitor (DBI)--a polypeptide that is abundant in steroidogenic cells--with glial mitochondrial DBI receptors (MDRs) is a crucial step in the physiological regulation of neurosteroid biosynthesis. MDRs bind 4'-chlorodiazepam (4'-CD), N,N-di-n-hexyl-2-(4-fluorophenyl)-indol-3-acetamide (FGIN-1-27), and the isoquinoline carboxamide PK 11195 with high affinity, and these ligands have been used to investigate whether the stimulation of glial MDRs increases brain pregnenolone production in vivo. Adrenalectomized and castrated (A-C) male rats (to eliminate peripheral sources of pregnenolone) were pretreated with trilostane (to prevent pregnenolone metabolism to progesterone), and the pregnenolone content in brain regions dissected after fixation with a 0.8-s exposure to microwave irradiation focused to the head was determined by HPLC followed by specific radioimmunoassay. The forebrain and cerebellum of A-C rats contained 4-7 ng of pregnenolone/g of tissue, and the olfactory bulb contained 10-14 ng/g. These concentrations of brain pregnenolone are only 30-40% lower than those of sham-operated rats. In contrast, the plasma pregnenolone content of sham-operated rats was 2-3 ng/ml, but it was only 0.15-0.20 ng/ml in the plasma of A-C rats. In A-C rats, treatment with the MDR ligands 4'-CD and FGIN-1-27 increased the pregnenolone content in the brain but failed to change the plasma or peripheral tissue content of this steroid. The effect of 4'-CD on brain pregnenolone content was maximal (70-100% increase) at the dose of 18 mumol/kg, 5-10 min after intravenous injection. The effect of oral administration of FGIN-1-27 on brain pregnenolone content was maximal (80-150% increase) at doses of 400-800 mumol/kg and peaked at approximately 1 h. That this effect of FGIN-1-27 was mediated by the MDR was documented by pretreatment with the MDR partial agonist PK 11195 (100 mumol/kg, i.p.). PK 11195 did not affect basal brain pregnenolone content but prevented the accumulation of brain pregnenolone induced by FGIN-1-27. FGIN-1-27 and 4'-CD failed to increase the brain concentration of dehydroepiandrosterone in A-C rats. These data suggest that glial cell MDRs play a role in neurosteroid biosynthesis in vivo.
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PMID:Stimulation of brain pregnenolone synthesis by mitochondrial diazepam binding inhibitor receptor ligands in vivo. 839 97

We investigated the role of the mitochondrial diazepam binding inhibitor receptor (MDR) in diazepam-withdrawal seizure. In chronically vehicle-treated mice, the potent and selective MDR agonist FGIN-1-27 (N,N-di-n-hexyl 2-(4-fluorophenyl)indole-3-acetamide: 30 microg/mouse, i.c.v.) markedly increased the threshold for pentylenetetrazole (PTZ)-induced seizure. The antiseizure effect of FGIN-1-27 was blocked by pretreatment with the selective MDR antagonist PK11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxa mide). In chronically diazepam-treated mice, the seizure threshold of PTZ was decreased during diazepam withdrawal, indicating withdrawal hyperexcitability. Interestingly, FGIN-1-27 (30 microg/mouse, i.c.v.) failed to increase the seizure threshold of PTZ in diazepam-withdrawn mice, in contrast to its effect in chronically vehicle-treated mice. These findings suggest that the sensitivity of MDR-mediated pathways in the brain may be decreased during diazepam withdrawal.
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PMID:Subsensitivity to mitochondrial diazepam binding inhibitor receptor agonist FGIN-1-27-induced antiseizure effect in diazepam-withdrawn mice. 957 Mar 45

The present study aimed to examine the antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha, 5alpha THP) using the forced swim test in mice. Intracerebroventricular (ICV, 1 or 2 microg/mouse) or intraperitoneal (IP, 0.5, 1, or 2 mg/kg) administration of 3alpha, 5alpha THP dose-dependently reduced the duration of immobility in forced swim test without accompanying changes in ambulatory or rearing behaviors in the open-field test. The antidepressant-like effect of 3alpha, 5alpha THP (1 microg/mouse, ICV) was potentiated by prior administration of the GABA(A) receptor agonist, muscimol (0. 5 mg/kg, IP) and blocked by prior administration of GABA(A) receptor antagonist, bicuculline (1 mg/kg, IP). Administration of the agonist at diazepam binding inhibitor receptors, 4'-chlorodiazepam (4'CD, 15 mg/kg, IP) or N,N-di-n-hexyl-2-(4-fluorophenyl)-indol-3-acetamide (FGIN 1-27, 1 or 2 microg/mouse, ICV), the 11beta-hydroxylase inhibitor, metyrapone (150 mg/kg, IP and 1 or 2 microg/mouse, ICV) and the selective serotonin reuptake inhibitor (SSRI), fluoxetine (20 mg/kg, IP), which are known to increase the endogenous level of neurosteroids, also reduced the duration of immobility in forced swim test. The tricyclic antidepressant, imipramine (20 mg/kg, IP), which does not increase the 3alpha, 5alpha THP in the brain, also reduced the immobility time. While the antidepressant-like effect of fluoxetine, which is known to selectively increase the brain content of 3alpha, 5alpha THP, was either blocked partially by bicuculline (1 mg/kg, IP) or potentiated by muscimol (0.5 mg/kg, IP), the antidepressant-like effect of imipramine was not modified by bicuculline. These results demonstrate the antidepressant-like effect of the neurosteroid 3alpha, 5alpha THP, and suggest further evaluation for its development as a new class of antidepressant drug.
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PMID:Antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in mice forced swim test. 1111 93

Peripheral-type benzodiazepine receptors (PBRs) are abundant in the cardiovascular system. In the cardiovascular lumen, PBRs are present in platelets, erythrocytes, lymphocytes, and mononuclear cells. In the walls of the cardiovascular system, PBR can be found in the endothelium, the striated cardiac muscle, the vascular smooth muscles, and the mast cells. The subcellular location of PBR is primarily in mitochondria. The PBR complex includes the isoquinoline binding protein (IBP), voltage-dependent anion channel (VDAC), and adenine nucleotide transporter (ANT). Putative endogenous ligands for PBR include protoporphyrin IX, diazepam binding inhibitor (DBI), triakontatetraneuropeptide (TTN), and phospholipase A2 (PLA2). Classical synthetic ligands for PBR are the isoquinoline 1-(2-chlorophenyl)-N-methyl-N-(1-methyl-propyl)-3-isoquinolinecarboxamide (PK 11195) and the benzodiazepine 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (Ro5 4864). Novel PBR ligands include N,N-di-n-hexyl 2-(4-fluorophenyl)indole-3-acetamide (FGIN-1-27) and 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575), both possessing steroidogenic properties, but while FGIN-1-27 is pro-apoptotic, SSR180575 is anti-apoptotic. Putative PBR functions include regulation of steroidogenesis, apoptosis, cell proliferation, the mitochondrial membrane potential, the mitochondrial respiratory chain, voltage-dependent calcium channels, responses to stress, and microglial activation. PBRs in blood vessel walls appear to take part in responses to trauma such as ischemia. The irreversible PBR antagonist, SSR180575, was found to reduce damage correlated with ischemia. Stress, anxiety disorders, and neurological disorders, as well as their treatment, can affect PBR levels in blood cells. PBRs in blood cells appear to play roles in several aspects of the immune response, such as phagocytosis and the secretion of interleukin-2, interleukin-3, and immunoglobulin A (IgA). Thus, alterations in PBR density in blood cells may have immunological consequences in the affected person. In conclusion, PBR in the cardiovascular system may represent a new target for drug development.
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PMID:The peripheral-type benzodiazepine receptor and the cardiovascular system. Implications for drug development. 1633 85