Negative Allosteric Modulators of mGlu7 Receptor as Putative Antipsychotic Drugs.

Paulina Cieślik,Agnieszka Chocyk,Grzegorz Burnat,Agnieszka Wąsik,Joanna Wierońska,Agnieszka Pałucha-Poniewiera,Katarzyna Kaczorowska,Piotr Gruca,Bartosz Bobula,Monika Woźniak,Andrzej Pilc,Ewa Litwa,Piotr Brański

doi:10.3389/fnmol.2018.00316

Paulina Cieślik, Agnieszka Chocyk + Show 11 more

Open Access

https://doi.org/10.3389/fnmol.2018.00316

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Abstract

The data concerning antipsychotic-like activity of negative allosteric modulators (NAMs)/antagonists of mGlu7 receptors are limited. The only available ligands for this receptor are MMPIP and ADX71743. In the present studies, we used stable cell line expressing mGlu7 receptor and it was shown that both compounds dose-dependently potentiated forskolin elevated cAMP concentration in the T-REx 293 cells, showing their inverse agonist properties. Subsequently, pharmacokinetic studies were performed. Both compounds were given intraperitoneally (i.p.) at the dose of 10 mg/kg and reached Cmax 0.25–0.5 h after administration, and then they declined rapidly, ADX71743 being almost undetectable 2 h after administration, while the concentration of MMPIP was still observed, suggesting that the concentration of MMPIP was more stable. Finally, we investigated the role of both mGlu7 receptor NAMs in animal models of schizophrenia. Behavioral tests commonly used in antipsychotic drug discovery were conducted. Both tested compounds dose-dependently inhibited MK-801-induced hyperactivity (MMPIP at 15 mg/kg; ADX at 5 and 15 mg/kg) and DOI-induced head twitches (MMPIP at 5, 10, 15 mg/kg; ADX at 2.5, 5, 10 mg/kg). Moreover, the same effects were noticed in novel object recognition test, where MMPIP (5, 10, 15 mg/kg) and ADX71743 (1, 5, 15 mg/kg) reversed MK-801-induced disturbances. In the social interaction test, antipsychotic activity was observed only for ADX71743 (5, 15 mg/kg). ADX71743 at the dose 2.5 mg/kg reversed MK-801-induced disruption in prepulse inhibition while MMPIP at 10 mg/kg reversed MK-801-induced disruption in spatial delayed alternation. The present studies showed that mGlu7 receptor may be considered as a putative target for antipsychotic drugs, though more studies are needed due to limited number of available ligands.

Highlights

Metabotropic glutamate receptors are being extensively studied as new pharmacological targets for central nervous system (CNS) disorders such as depression (Mitsukawa et al, 2006), anxiety (Swanson et al, 2005), schizophrenia (Conn et al, 2009; Nickols and Conn, 2014), neurodegenerative disorders (Gu et al, 2014; Litim et al, 2017), and pain (Acher and Goudet, 2015; Chiechio, 2016)
In order to confirm the negative allosteric modulators (NAMs) profile of ADX71743 and MMPIP, the substances were incubated with 6.26 mM of L-Glu (EC80)
In the second set of experiments the cells were incubated with forskolin with increasing concentration of ADX71743 or MMPIP without agonist in order to analyze their inverse agonist properties

Summary

Introduction

Metabotropic glutamate receptors (mGluR) are being extensively studied as new pharmacological targets for central nervous system (CNS) disorders such as depression (Mitsukawa et al, 2006), anxiety (Swanson et al, 2005), schizophrenia (Conn et al, 2009; Nickols and Conn, 2014), neurodegenerative disorders (Gu et al, 2014; Litim et al, 2017), and pain (Acher and Goudet, 2015; Chiechio, 2016). It was shown that AMN082 possesses antidepressantlike profile in FST and TST, and anxiolytic properties in four plate test and stress-induced hyperthermia (Palucha et al, 2007; Stachowicz et al, 2008) It did not exhibit any antipsychotic-like profile and rather enhanced MK-801- or DOIinduced effects, which may suggest a potential beneficial role of antagonists or negative allosteric modulators (NAMs) in animal models of schizophrenia (Wieronska et al, 2012). Some studies reported off target activity of AMN082 (Sukoff Rizzo et al, 2011)

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