title: 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,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 (t(1/2) < 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.
authors.affiliation: Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut 06340, USA. stacey.rizzo@pfizer.com
authors.forename: Stacey J
authors.initials: SJ
authors.lastname: Sukoff Rizzo
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Leonard
authors.forename: Adam
authors.initials: A
authors.lastname: Gilbert
authors.forename: Paul
authors.initials: P
authors.lastname: Dollings
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Smith
authors.forename: Mei-Yi
authors.initials: MY
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Di
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Platt
authors.forename: Sarah
authors.initials: S
authors.lastname: Neal
authors.forename: Jason M
authors.initials: JM
authors.lastname: Dwyer
authors.forename: Corey N
authors.initials: CN
authors.lastname: Bender
authors.forename: Jean
authors.initials: J
authors.lastname: Zhang
authors.forename: Tim
authors.initials: T
authors.lastname: Lock
authors.forename: Dianne
authors.initials: D
authors.lastname: Kowal
authors.forename: Angela
authors.initials: A
authors.lastname: Kramer
authors.forename: Andrew
authors.initials: A
authors.lastname: Randall
authors.forename: Christine
authors.initials: C
authors.lastname: Huselton
authors.forename: Karthick
authors.initials: K
authors.lastname: Vishwanathan
authors.forename: Susanna Y
authors.initials: SY
authors.lastname: Tse
authors.forename: John
authors.initials: J
authors.lastname: Butera
authors.forename: Robert H
authors.initials: RH
authors.lastname: Ring
authors.forename: Sharon
authors.initials: S
authors.lastname: Rosenzweig-Lipson
authors.forename: Zoë A
authors.initials: ZA
authors.lastname: Hughes
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001559:Benzhydryl Compounds / Q000378:metabolism / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000494:pharmacology* / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000502:physiology*
chemical_list: D001559:Benzhydryl Compounds; D015306:Biogenic Monoamines; C507346:N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7