AMN 082 dihydrochloride

AMN 082 dihydrochloride is an specific allosteric agonist of mGluR7 [1]. In the absence of orthosteric agonist, AMN 082 activated the human mGlu7 receptor with an EC50 of 64 nM in vitro [2].

MGlu receptors belong to the family 3 G-protein coupled receptors (GPCRs) [2]. The GPCR metabotropic glutamate receptor 7 (mGluR7) is widely expressed in the nervous system. MGluR7 is implicated in many physiological processes such as synaptic plasticity and neuroprotection [1].

Dissociated hippocampal cultured neurons had been transfected with N-terminally myc-tagged mGluR7a were used in the assay. In these neurons, treatment with AMN082 at concentrations ranging from 0.5-1 µM strikingly caused robust mGluR7 internalization. The receptor internalization was increased to 291 ± 30% of control levels. The binding site of AMN082 on mGluR7 is distinct from the glutamate binding pocket on the receptor, conventional competitive antagonists are not able to prevent the activation of the allosteric agonist to the receptor [1].

In vivo, treatment with AMN082 was shown to penetrate into the brain and hence it modulated the level of stress hormones (ACTH and cortisol) in wild type animal. But these effects were not found in the mGluR7 ko mouse [2].

References:
[1].  Pelkey KA, Yuan X, Lavezzari G, et al. mGluR7 undergoes rapid internalization in response to activation by the allosteric agonist AMN082. Neuropharmacology, 2007, 52(1): 108-117.
[2].  Gasparini F, Spooren W. Allosteric modulators for mGlu receptors. Current neuropharmacology, 2007, 5(3): 187-194.

Metabotropic glutamate 7 receptor subtype modulates motor symptoms in rodent models of Parkinson's disease.[Pubmed:19940105]

J Pharmacol Exp Ther. 2010 Mar;332(3):1064-71.

Metabotropic glutamate (mGlu) receptors modulate synaptic transmission in the central nervous system and represent promising therapeutic targets for symptomatic treatment of Parkinson's disease (PD). Among the eight mGlu receptor subtypes, mGlu7 receptor is prominently expressed in the basal ganglia, but its role in restoring motor function in animal models of PD is not known. The effects of N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), the first selective allosteric activator of mGlu7 receptors, were thus tested in different rodent models of PD. Here, we show that oral (5 mg/kg) or intrastriatal administration (0.1 and 0.5 nmol) of AMN082 reverses haloperidol-induced catalepsy in rats. AMN082 (2.5 and 5 mg/kg) reduces apomorphine-induced rotations in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. In a more complex task commonly used to evaluate major akinetic symptoms of PD patients, 5 mg/kg AMN082 reverses the increased reaction time to respond to a cue of bilateral 6-OHDA-lesioned rats. In addition, AMN082 reduces the duration of haloperidol-induced catalepsy in a mGlu7 receptor-dependent manner in wild-type but not mGlu7 receptor knockout mice. Higher doses of AMN082 (10 and 20 mg/kg p.o.) have no effect on the same models of PD. Overall these findings suggest that mGlu7 receptor activation can reverse motor dysfunction associated with reduced dopamine activity. Selective ligands of mGlu7 receptor subtypes may thus be considered as promising compounds for the development of antiparkinsonian therapeutic strategies.