A Selective Allosteric Potentiator of Metabotropic Glutamate (mGlu) 2 Receptors Has Effects Similar to an Orthosteric mGlu2/3 Receptor Agonist in Mouse Models Predictive of Antipsychotic Activity

Abstract

Recent studies suggest that agonists of group II metabotropic glutamate (mGlu) receptors (mGlu2/3) have potential utility as novel therapeutic agents for treatment of psychiatric disorders such as anxiety and schizophrenia. Agonists of mGlu2/3 receptors block amphetamine-and phencyclidine (PCP)-induced hyperlocomotor activity in rodents, two actions that may predict potential antipsychotic activity of these compounds. We now report that LY487379 [N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine], a recently described selective allosteric potentiator of mGlu2 receptor, has behavioral effects similar to mGlu2/3 receptor agonists. LY487379 and LY379268 [(Ϫ)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate], an ortho-steric mGlu2/3 receptor agonist, induced similar dosedependent reductions in PCP-and amphetamine-induced hyperlocomotor activity in C57BL6/J mice at doses that did not significantly alter spontaneous locomotor activity. These effects were blocked by the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid]. LY487379 had a short duration of action compared with LY379268. Furthermore, unlike the mGlu2/3 agonist, LY487379 reversed amphetamine-induced disruption of prepulse inhibition of the acoustic startle reflex. When LY379268 was given chronically, it failed to block amphetamine-and PCP-induced hyperlocomotor activity. The finding that the effects of an orthosteric mGlu2/3 receptor agonist in these models can be mimicked by a selective allosteric potentiator of mGlu2 suggests that these effects are mediated by the mGlu2 receptor subtype. Furthermore, these data raise the possibility that a selective allosteric potentiator of mGlu2 receptor could have utility as a novel approach for the treatment of schizophrenia.

Chronic Phenethylamine Hallucinogen Treatment Alters Behavioral Sensitivity to a Metabotropic Glutamate 2/3 Receptor Agonist

“…To test for potential desensitization of mGlu2/3 receptors by the repeated (À)-DOB treatment in the discrimination paradigm, we compared the ability of an mGlu2/3 receptor agonist to modulate (À)-DOB-induced HTR and PCPinduced hyperlocomotion in drug-naive vs mice trained in the drug discrimination paradigm. The group II mGlu receptor agonist LY379268 produces a dose-dependent blockade in both of these behaviors in drug-naive mice, in agreement with previous studies (Klodzinska et al, 2002;Galici et al, 2005). Conversely, the behavioral actions of LY379268 are blunted in mice trained to discriminate (À)-DOB from saline, with a complete lack of attenuation of the (À)-DOB-induced HTR and a reduced potency to block PCP-induced hyperlocomotion.…”

“…Previous work has demonstrated the ability of mGlu2/3 receptor activation to attenuate PCP-induced hyperlocomotion (Moghaddam and Adams, 1998;Cartmell et al, 1999;Galici et al, 2005). Two doses of LY379268 (3.0 and 10 mg/kg) and saline were tested in combination with PCP (5.6 mg/kg) in drug-naive and (À)-DOB-trained mice.…”

Positive Allosteric Modulators for mGluR2 Receptors: A Medicinal Chemistry Perspective

“…In addition, the allosteric binding sites on glutamate receptors might sufficiently be different as to make subgroup selectivity achievable [21]. In fact, the preclinical proof of concept was achieved by LY487379, the first mGluR2 receptor-specific PAM [22] showing efficacy in animal models of schizophrenia [23,24]. More recently the Addex-J&J team reported the first successful clinical proof of concept study with ADX-71149 (also known as JNJ-4041183).…”

“…Compound 3, also known as BINA [33] is a representative structure of this indanone series (Figure 2). BINA, together with LY487379, is among the first mGluR2 potentiators showing antipsychotic-and anxiolytic like effects in vivo [34,35]. Detailed SAR of this series is also published separately in two medicinal chemistry papers [33,36].…”

Study of Novel Selective mGlu2 Agonist in the Temporo-Ammonic Input to CA1 Neurons Reveals Reduced mGlu2 Receptor Expression in a Wistar Substrain with an Anxiety-Like Phenotype

“…N-acetylaspartylglutamate (NAAG) and ␤-NAAG have been reported as selective mGlu3 ligands (Wroblewska et al, 1997), but there are concerns with the use of NAAG (Fricker et al, 2009). There are selective positive allosteric modulators of mGlu2, but these require agonist activation of the receptor to show effects (Johnson et al, 2003;Galici et al, 2005). Clearly, additional subtype-selective compounds are required.…”