Abstract
Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ35S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca2+ mobilization assay. SAR218645 potentiated mGluR2 agonist-induced contralateral turning. When SAR218645 was tested in models of the positive symptoms of schizophrenia, it reduced head twitch behavior induced by DOI, but it failed to inhibit conditioned avoidance and hyperactivity using pharmacological and transgenic models. Results from experiments in models of the cognitive symptoms associated with schizophrenia showed that SAR218645 improved MK-801-induced episodic memory deficits in rats and attenuated working memory impairment in NMDA Nr1neo−/− mice. The drug reversed disrupted latent inhibition and auditory-evoked potential in mice and rats, respectively, two endophenotypes of schizophrenia. This profile positions SAR218645 as a promising candidate for the treatment of cognitive symptoms of patients with schizophrenia, in particular those with abnormal attention and sensory gating abilities.
Highlights
These drugs[9,10]
While these findings point towards a beneficial role of mGluR2/3 agonists against the positive symptoms of schizophrenia, other studies in rodents have indicated that these compounds may have an additional potential to treat the cognitive symptoms of this condition, the results have been inconsistent throughout the studies
Activation of mGluR2 was assessed by measuring glutamate-induced increases in intracellular calcium in HEK293 cells expressing rat mGluR2 coexpressed with the G protein (Gα1 6)
Summary
These drugs[9,10]. While these findings point towards a beneficial role of mGluR2/3 agonists against the positive symptoms of schizophrenia, other studies in rodents have indicated that these compounds may have an additional potential to treat the cognitive symptoms of this condition, the results have been inconsistent throughout the studies (see ref. 7 for a review of these findings). Selective PAMs of the mGluR2 with structural diversity have been identified[14,18] They have been reported to display antipsychotic-like activity in various rodent models, including psychostimulant-induced hyperlocomotion or disruption of prepulse inhibition of the acoustic startle reflex, and conditioned avoidance behavior[15,19,20,21,22,23,24]. In an exploratory study in stably treated patients with schizophrenia, the mGluR2 PAM, JNJ-40411813, was found to attenuate ketamine-induced increases in Brief Psychiatric Rating Scale scores mostly via an effect on negative symptoms[25] Together, these findings suggest that mGluR2 PAMs may offer a beneficial therapeutic approach for the treatment of schizophrenia. We suggest a possible translational approach for initial clinical studies
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