ADX71743, a Potent and Selective Negative Allosteric Modulator of Metabotropic Glutamate Receptor 7: In Vitro and In Vivo Characterization

Abstract

Metabotropic glutamate receptor 7 (mGlu 7 ) has been suggested to be a promising novel target for treatment of a range of disorders, including anxiety, post-traumatic stress disorder, depression, drug abuse, and schizophrenia. Here we characterized a potent and selective mGlu 7 negative allosteric modulatorIn vitro, Schild plot analysis and reversibility tests at the target confirmed the NAM properties of the compound and attenuation of L-(1)-2-amino-4-phosphonobutyric acid-induced synaptic depression confirmed activity at the native receptor. The pharmacokinetic analysis of ADX71743 in mice and rats revealed that it is bioavailable after s.c. administration and is brain penetrant (cerebrospinal fluid concentration/ total plasma concentration ratio at C max 5 5.3%). In vivo, ADX71743 (50, 100, 150 mg/kg, s.c.) caused no impairment of locomotor activity in rats and mice or activity on rotarod in mice.ADX71743 had an anxiolytic-like profile in the marble burying and elevated plus maze tests, dose-dependently reducing the number of buried marbles and increasing open arm exploration, respectively. Whereas ADX71743 caused a small reduction in amphetamine-induced hyperactivity in mice, it was inactive in the mouse 2,5-dimethoxy-4-iodoamphetamineinduced head twitch and the rat conditioned avoidance response tests. In addition, the compound was inactive in the mouse forced swim test. These data suggest that ADX71743 is a suitable compound to help unravel the physiologic role of mGlu 7 and to better understand its implication in central nervous system diseases. Our in vivo tests using ADX71743, reported here, suggest that pharmacological inhibition of mGlu 7 is a valid approach for developing novel pharmacotherapies to treat anxiety disorders, but may not be suitable for treatment of depression or psychosis.

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

“…The nonselective agonist L-AP4, which also interacts with other group III mGlu subtypes, and AMN082, an allosteric agonist but at the same time a strong inducer of mGlu7 internalization, were the main tools available (24,39,62). More recently, different mGlu7-selective NAMs have been reported (26,29), which blocked mGlu7 selectively in recombinant cells. However, a stringent assessment of their mGlu7-dependent action in native brain tissues and assays is still missing.…”

“…Mice were anesthetized with isoflurane and sacrificed by decapitation. The skull covering the cortex was removed, and the brain was quickly excised and placed in ice-cold artificial cerebrospinal fluid equilibrated with 95% O 2 , 5% CO 2 containing (in mM) the following: NaCl (124), KCl (2.5), KH 2 PO 4 (1.2), CaCl 2 (2.5), MgSO 4 (1.3), NaHCO 3 (26), glucose (10), and saccharose (4). Osmolarity was adjusted to 320 Ϯ 2 mosM by reducing the amount of H 2 O, and pH was set to 7.4.…”

“…ADX71743 (26) was shown to have robust anxiolytic-like effects in the elevated plus-maze (EPM) and the marble burying test. In contrast, MMPIP (27)(28)(29) showed no effects in a battery of anxiety-like and depressionrelated tests but was active in spatial learning tasks.…”

Characterization of the Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 ADX88178 in Rodent Models of Neuropsychiatric Disorders

“…The procedure was performed as described previously (Kalinichev et al, 2013). Male mice (n 5 8-10/group) were treated orally (p.o.)…”

“…Adult male Wistar rats, purchased from Charles River and maintained at RenaSci Ltd. under standard laboratory conditions, were used in this experiment. The test was performed as described previously (Kalinichev et al, 2013). One week after the last validation experiment with an antipsychotic drug, animals (n 5 8/group) were administered p.o.…”