Metabotropic glutamate receptor 7 (mGluR7) remains the most elusive of the eight known mGluRs primarily due to the limited availability of tool compounds to interrogate its potential therapeutic utility. The recent discovery of AMN082 as the first orally active, brain penetrable, mGluR7 selective allosteric agonist by Mitsukawa and colleagues (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 (T1/2< 1min) 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 SERT, DAT and NET (323, 3020, and 3410 nM respectively); while the parent compound AMN082 had appreciable affinity at NET (1385 nM). AMN082 produced antidepressant-like activity and receptor occupancy at SERT up to 4 hours post dose, 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, as they may involve other mechanisms in addition to mGluR7.
- Received November 21, 2010.
- Revision received April 11, 2011.
- Accepted April 12, 2011.
- The American Society for Pharmacology and Experimental Therapeutics