No abstract

Current pharmacotherapies for depression exhibit slow onset, side effects and limited efficacy. Therefore, identification of novel fast-onset antidepressants is desirable. GLO1 is a ubiquitous cellular enzyme responsible for the detoxification of the glycolytic byproduct methylglyoxal (MG). We have previously shown that MG is a competitive partial agonist at GABA-A receptors. We examined the effects of genetic and pharmacological inhibition of GLO1 in two antidepressant assay models: the tail suspension test (TST) and the forced swim test (FST). We also examined the effects of GLO1 inhibition in three models of antidepressant onset: the chronic FST (cFST), chronic mild stress (CMS) paradigm, and olfactory bulbectomy (OBX). Genetic knockdown of Glo1 or pharmacological inhibition using two structurally distinct GLO1 inhibitors (S-bromobenzylglutathione cyclopentyl diester (pBBG) or methyl gerfelin (MeGFN)) reduced immobility in the TST and acute FST. Both GLO1 inhibitors also reduced immobility in the cFST after 5 days of treatment. In contrast, the serotonin reuptake inhibitor fluoxetine (FLX) reduced immobility after 14, but not 5 days of treatment. Furthermore, 5 days of treatment with either GLO1 inhibitor blocked the depression-like effects induced by CMS on the FST and coat state, and attenuated OBX-induced locomotor hyperactivity. Finally, 5 days of treatment with a GLO1 inhibitor (pBBG), but not FLX, induced molecular markers of the antidepressant response including brain-derived neurotrophic factor (BDNF) induction and increased phosphorylated cyclic-AMP response binding protein (pCREB) to CREB ratio in the hippocampus and medial prefrontal cortex (mPFC). Our findings indicate that GLO1 inhibitors may provide a novel and fast-acting pharmacotherapy for depression.

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Starting with the title compound (I), the β‐carboline derivatives (II) and (IV) are prepared by known procedures.

The conversion of the 4-oxo-2-benzoyl-l,2,3,4-tetrahydro-|8-carbolines la and lb, respectively, into their corresponding 4-amino-(3-carbolines 2a and 2b was effected in 70% yield in refluxing hydrazine. In contrast, phenylhydrazine, when heated with the 4-oxo derivative lb, gave the pyridodiindole 18a. This compound derives its origin from an initial Fischer indole cyclization, followed by loss of the 2-benzoyl group and aromatization to the /3-carboline. During investigation of the scope and mechanism of this new amination-oxidation reaction, it was found that an acidic hydrogen atom (position 2, NH) to the carbonyl group (C-4) was necessary to drive the reaction to completion. Although phenylhydrazones such as 20b and 20c, which carry electron-withdrawing groups, led to the formation of 2b at the expense of the Fischer indole products 18b and 18c, respectively, the yields in this sequence were only moderate. Hydrazine, consequently, appears to be the reagent of choice to effect this amination-oxidation reaction since Fischer indole cyclization cannot compete in this process.