N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a Novel Metabotropic Glutamate 2 Potentiator with Potential Anxiolytic/Antidepressant Properties: In Vivo Profiling Suggests a Link between Behavioral and Central Nervous System Neurochemical Changes

Abstract

The normalization of excessive glutamatergic neurotransmission through the activation of metabotropic glutamate 2 (mGlu2) receptors may have therapeutic potential in a variety of psychiatric disorders, including anxiety/depression and schizophrenia. Here, we characterize the pharmacological properties of N- (4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a structurally novel, potent, and selective allosteric potentiator of human and rat mGlu2 receptors (EC 50 ϭ 23 and 13 nM, respectively). THIIC produced anxiolytic-like efficacy in the rat stress-induced hyperthermia assay and the mouse stress-induced elevation of cerebellar cGMP and marble-burying assays. THIIC also produced robust activity in three assays that detect antidepressant-like activity, including the mouse forced-swim test, the rat differential reinforcement of low rate 72-s assay, and the rat dominant-submissive test, with a maximal response similar to that of imipramine. Effects of THIIC in the forced-swim test and marble burying were deleted in mGlu2 receptor null mice. Analysis of sleep electroencephalogram (EEG) showed that THIIC had a sleeppromoting profile with increased non-rapid eye movement (REM) and decreased REM sleep. THIIC also decreased the dark phase increase in extracellular histamine in the medial prefrontal cortex and decreased levels of the histamine metabolite tele-methylhistamine (t-MeHA) in rat cerebrospinal fluid. Collectively, these results indicate that the novel mGlu2-positive allosteric modulator THIIC has robust activity in models used to predict anxiolytic/antidepressant efficacy, substantiating, at least with this molecule, differentiation in the biological impact of mGlu2 potentiation versus mGlu2/3 orthosteric agonism. In addition, we provide evidence that sleep EEG and CSF t-MeHA might function as viable biomarker approaches to facilitate the translational development of THIIC and other mGlu2 potentiators.

L -acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors

“…The lack of subtype-selectivity of MGS0039 and LY379268 may confound the interpretation of these findings. Recent evidence shows that a selective mGlu2 receptor enhancer produces antidepressant effects (45), and here, LAC relieved depressive symptoms by selectively inducing mGlu2 receptors. A potential involvement of mGlu3 receptors in the pathophysiology of depression is suggested by the association between a polymorphic variant of Grm3 (the gene encoding the mGlu3 receptor) and MDD (46).…”

Positive Allosteric Modulators for mGluR2 Receptors: A Medicinal Chemistry Perspective

“…These derivatives are exemplified with compound 9, as a potent mGluR2 PAM with an EC 50 value of 26 nM in FLIPR assay. A detailed in vivo profile of this compound, also known as THIIC, was given in a separate literature [47]. …”

Depression Viewed as a GABA/Glutamate Imbalance in the Central Nervous System

“…The compound was shown to be an effective anxiolytic, but not an antidepressant agent after peripheral administration in animal studies (Klodzinska et al, 1999). However, data on the antidepressant action of a novel mGlu 2 receptor potentiator THIIC (Fell et al, 2011) was recently reported, creating a hope for the antidepressant-like action for subtype selective agonists/PAMs. Table 3 a number of experiments described the antidepressant-like activity of ligands of the mGlu 2/3 receptors.…”