FGIN-1-27

In the ventral tegmental area picrotoxin blocks FGIN 1-27-induced increases in sexual behavior of rats and hamsters.[Pubmed:15338106]

Psychopharmacology (Berl). 2005 Mar;178(2-3):174-82.

RATIONALE AND OBJECTIVES: There are two types of benzodiazepine receptors, mitochondrial benzodiazepine receptors (MBRs), and gamma-aminobutyric acid (GABA(A))/benzodiazepine receptor complexes (GBRs). MBR activation increases neurosteroidogenesis. Ventral tegmental area (VTA) infusions of the MBR agonist, FGIN 1-27, increase midbrain levels of the progesterone metabolite 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) and lordosis of rats and hamsters. Activation of GBRs leads to membrane hyperpolarization. In the VTA, infusions of GBR agonists enhance 3alpha,5alpha-THP-facilitated lordosis. Thus, if, in the VTA, MBR-mediated increases in 3alpha,5alpha-THP enhance sexual responses via actions at GBRs, then blocking GBRs with picrotoxin will reduce FGIN 1-27-induced increases in sexual behavior of female rodents. METHODS: Ovariectomized rats and hamsters, with unilateral guide cannula to the VTA, received estradiol benzoate (10 mug; EB) at hour 0. Hamsters also received progesterone (100 mug) at hour 44. At hour 47.5, all animals were infused first with 10 ng or 20 ng picrotoxin or saline, vehicle to the VTA and, 30 min later, with 5 mug/11.4 nM FGIN 1-27 or saline, vehicle. Ten minutes later, animals were tested for sex and motor behavior. RESULTS: Picrotoxin, but not vehicle, infusions blocked FGIN 1-27-mediated increases in lordosis of rats and hamsters, proceptivity of rats, and sexual responsiveness of hamsters. In addition, midbrain 3alpha,5alpha-THP levels were higher in animals that received VTA infusions of FGIN 1-27, compared to those infused with saline, vehicle. CONCLUSION: In the VTA, GBRs are required for MBR-enhanced sexual behavior of EB-primed rats and EB- and progesterone-primed hamsters.

Preparation of indoles from alpha-aminonitriles: A short synthesis of FGIN-1-27.[Pubmed:16986928]

Org Lett. 2006 Sep 28;8(20):4473-5.

Alpha-Aminonitriles derived from 2-aminocinnamic acid esters and amides can be cyclized under basic conditions to furnish substituted indole-3-acetic acid derivatives in quantitative yield. The reaction provides a simple access to a class of biologically active compounds.

In vitro effect of FGIN-1-27, a ligand to 18 kDa mitochondrial translocator protein, in human osteoblast-like cells.[Pubmed:24532136]

J Bioenerg Biomembr. 2014 Jun;46(3):197-204.

Ligands of 18 kDa mitochondrial translocator protein (TSPO) differ in their cellular effects. We hypothesize that different TSPO ligands might exert different cellular responses. Therefore, following previous studies that showed different cellular responses to two specific TSPO ligands, PK 11195 and protoporphyrin IX, in human osteoblast-like cells in vitro, we now report the cellular response to another specific TSPO ligand, FGIN-1-27 (10(-5) M) (MW 436 kDa), in order to characterize the effects of each TSPO ligand. We found in primary culture of the human osteoblast-like cells that cell numbers were decreased by an average of 30% (p < 0.001) following exposure to 10(-5) M of FGIN-1-27 in comparison to vehicle controls. Cellular [(18)F]-FDG incorporation and ATP content were suppressed, by an average of 43% (p < 0.001) and 83% (p < 0.001), respectively. Mitochondrial mass and DeltaPsim increased by an average of 26% (p < 0.01) and 425% (p < 0.0001) respectively. Lactate dehydrogenase activity was enhanced in culture media by 60% (p < 0.05), indicating overall cell death, while no increase in apoptotic levels was observed. Cellular proliferation, as determined by BrdU assay, was not affected. Synthesis of mRNA of TSPO, VDAC 1, and hexokinase 2 decreased in 0.3, 0.3 and 0.5 fold respectively, with accompanying decreases in protein expression of TSPO and Voltage Dependent Anion Channel 1 by 23% (p < 0.001) and 98% (p < 0.001), respectively, but without changes in hexokinase 2 protein expression. Thus it appears that 10(-5) M FGIN-1-27 reduces cell viability, cell metabolism, and mitochondrial function. Previously we found similar effects of PK 11195 on mitochondrial function and cell metabolism and of protoporphyrin IX on cell death in primary osteoblast-like cells.

Synthesis and preliminary behavioural evaluation in mice of new 3-aryl-3-pyrrol-1-ylpropanamides, analogues of FGIN-1-27 and FGIN-1-43.[Pubmed:11732760]

J Pharm Pharmacol. 2001 Nov;53(11):1561-8.

The 2-aryl-3-indoleacetamides FGIN-1-27 and FGIN-1-43 have already been characterized in-vitro as potent and specific ligands for the mitochondrial DBI receptor. This affinity was associated with psychotropic properties in several rodent behavioural tasks (in particular anxiolytic action) via enhancement of GABA transmission through neurosteroid production. The synthesis of new 3-aryl-3-pyrrol-1-ylpropanamides 1a-i, analogues of FGIN-1-27 and FGIN-1-43, is described in four steps starting from the corresponding arylaldehydes. Preliminary evaluation of these compounds in behavioural studies (spontaneous locomotor activity and anxiolytic activity) in mice was also undertaken.

2-Aryl-3-indoleacetamides (FGIN-1): a new class of potent and specific ligands for the mitochondrial DBI receptor (MDR).[Pubmed:1326631]

J Pharmacol Exp Ther. 1992 Sep;262(3):971-8.

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.