The mGluR2 positive allosteric modulator, SAR218645, improves memory and attention deficits in translational models of cognitive symptoms associated with schizophrenia.

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 GTPγ ³⁵ S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca ²⁺ 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 Nr1 ^neo-/- 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.
Competing Interests: Organizations from whom the authors have received compensation for professional services: Guy Griebel, employee of Sanofi; Philippe Pichat, employee of Sanofi; Vanessa Naimoli, former employee of Sanofi; Lisa Potestio, former employee of Sanofi; Robert Featherstone, former employee of Sanofi; Sukhveen Sahni, former employee of Sanofi; Henry Defex, former employee of Sanofi; Christophe Desvignes, employee of Sanofi; Franck Slowinski, employee of Sanofi; Xavier Vigé, employee of Sanofi; Olivier E. Bergis, employee of Sanofi; Rosy Sher, former employee of Sanofi; Raymond Kosley, former employee of Sanofi; Sathapana Kongsamut, former employee of Sanofi; Mark D. Black, former employee of Sanofi; Geoffrey B. Varty, former employee of Sanofi. Drs Kosley and Sher are inventors on a patent covering the main product described in this report.