PT  - JOURNAL ARTICLE
AU  - Stacey J. Sukoff Rizzo
AU  - Sarah K. Leonard
AU  - Adam Gilbert
AU  - Paul Dollings
AU  - Deborah L. Smith
AU  - Mei-Yi Zhang
AU  - Li Di
AU  - Brian J. Platt
AU  - Sarah Neal
AU  - Jason M. Dwyer
AU  - Corey N. Bender
AU  - Jean Zhang
AU  - Tim Lock
AU  - Dianne Kowal
AU  - Angela Kramer
AU  - Andrew Randall
AU  - Christine Huselton
AU  - Karthick Vishwanathan
AU  - Susanna Y. Tse
AU  - John Butera
AU  - Robert H. Ring
AU  - Sharon Rosenzweig-Lipson
AU  - Zoë A. Hughes
AU  - John Dunlop
TI  - The Metabotropic Glutamate Receptor 7 Allosteric Modulator AMN082: A Monoaminergic Agent in Disguise?
AID  - 10.1124/jpet.110.177378
DP  - 2011 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 345--352
VI  - 338
IP  - 1
4099  - http://jpet.aspetjournals.org/content/338/1/345.short
4100  - http://jpet.aspetjournals.org/content/338/1/345.full
SO  - J Pharmacol Exp Ther2011 Jul 01; 338
AB  - 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,N′-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 (t1/2 < 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.