The Metabotropic Glutamate Receptor 7 Allosteric Modulator AMN082: A Monoaminergic Agent in Disguise?

Abstract

Metabotropic glutamate receptor 7 (mGluR7) remains the most elusive of the eight known mGluRs primarily because of the limited availability of tool compounds to interrogate its potential therapeutic utility. The discovery of N,NЈ-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) as the first orally active, brain-penetrable, mGluR7-selective allosteric agonist by Mitsukawa and colleagues (Proc Natl Acad Sci USA 102:18712-18717, 2005) provides a means to investigate this receptor system directly. AMN082 demonstrates mGluR7 agonist activity in vitro and interestingly has a behavioral profile that supports utility across a broad spectrum of psychiatric disorders including anxiety and depression. The present studies were conducted to extend the in vitro and in vivo characterization of AMN082 by evaluating its pharmacokinetic and metabolite profile. Profiling of AMN082 in rat liver microsomes revealed rapid metabolism (t 1/2 Ͻ 1 min) to a major metabolite, N-benzhydrylethane-1,2-diamine (Met-1). In vitro selectivity profiling of Met-1 demonstrated physiologically relevant transporter binding affinity at serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) (323, 3020, and 3410 nM, respectively); whereas the parent compound AMN082 had appreciable affinity at NET (1385 nM). AMN082 produced antidepressant-like activity and receptor occupancy at SERT up to 4 h postdose, a time point at which AMN082 is significantly reduced in brain and plasma while the concentration of Met-1 continues to increase in brain. Acute Met-1 administration produced antidepressant-like activity as would be expected from its in vitro profile as a mixed SERT, NET, DAT inhibitor. Taken together, these data suggest that the reported in vivo actions of AMN082 should be interpreted with caution, because they may involve other mechanisms in addition to mGluR7.

Identification of Novel Radiosensitizers in a High-Throughput, Cell-Based Screen for DSB Repair Inhibitors

“…As discussed earlier, GBM tumors would be an ideal target to test such agents, since they are exquisitely radioresistant tumors, and local recurrence is the predominant mode of failure for these tumors (62). Drugs in our hit-list such as mibefradil, pimozide and AMN082 are of particular interest for the treatment of brain tumors, because they are known to penetrate the blood brain barrier (75–77). Intriguingly, mibefradil has been shown to synergize with both temozolomide chemotherapy and IR, both in vitro in glioma cell lines, and in vivo in mouse GBM xenografts (78–80).…”

Blocking Metabotropic Glutamate Receptor Subtype 7 (mGlu7) via the Venus Flytrap Domain (VFTD) Inhibits Amygdala Plasticity, Stress, and Anxiety-related Behavior

“…Also, AMN082 has been shown to induce a rapid and long-lasting internalization of mGlu7 receptors, which could translate into functional antagonism of the receptor (24). Furthermore, the primary metabolite of AMN082, N-benzhydrylethane-1,2-diamine, inhibits serotonin and norepinephrine reuptake transporters (24,25). Altogether, these findings may explain the seemingly conflicting results obtained using AMN082 in vivo.…”

Metabotropic Glutamate Receptor 7 (mGluR7) as a Target for the Treatment of Psychostimulant Dependence

“…Thus, we investigated the involvement of mGluR7 in psychostimulant dependence using these two compounds. Notably, after we published papers that reported the effects of AMN082 on cocaine dependence, subsequent studies indicated that some of the effects of AMN082 may not be attributable to mGluR7 but rather to monoamine reuptake inhibition by an AMN082 metabolite [28, 29]. However, in our cocaine studies, AMN082 was centrally injected into specific brain sites, thus avoiding the nonspecific effects induced by the metabolite.…”

“…As the most widely distributed Group III subtype, mGluR7 appears to be engaged in these actions. Accumulating evidence indicates that mGluR7 may be a promising target for the development of novel therapeutics to treat depression and anxiety [29, 41, 67–69]. …”

“…AMN082 produced anxiolytic-like effects in the modified stress-induced hyperthermia and four-plate test in wildtype, but not mGluR7 knockout, mice [70], impaired conditioned fear learning and enhanced its extinction [71–73], and facilitated between-session fear extinction [74]. AMN082 was also shown to have antidepressant-like effects in the forced swim and tail suspension tests in both mice and rats [29, 41, 67–69]. However, these pharmacological findings with AMN082 contradict those that used genetic manipulations and novel recently synthesized mGluR7 antagonists.…”