title: The mGluR2 positive allosteric modulator, SAR218645, improves memory and attention deficits in translational models of cognitive symptoms associated with schizophrenia.
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.
authors.affiliation: Sanofi R&D, Strategy, Science Policy &amp;External Innovation, Chilly-Mazarin, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Griebel
authors.affiliation: Sanofi R&D, Translational Sciences Unit, Chilly-Mazarin, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pichat
authors.affiliation: Sanofi R&D, Translational Sciences Unit, Chilly-Mazarin, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Boulay
authors.affiliation: Sanofi R&D, 1041 Route 202/206, Bridgewater, NJ, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Naimoli
authors.affiliation: Sanofi R&D, 1041 Route 202/206, Bridgewater, NJ, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Potestio
authors.affiliation: Sanofi R&D, 1041 Route 202/206, Bridgewater, NJ, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Featherstone
authors.affiliation: Sanofi R&D, 1041 Route 202/206, Bridgewater, NJ, USA.
authors.forename: Sukhveen
authors.initials: S
authors.lastname: Sahni
authors.affiliation: Sanofi R&D, 1041 Route 202/206, Bridgewater, NJ, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Defex
authors.affiliation: Sanofi R&D, Analytical Sciences, Montpellier, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Desvignes
authors.affiliation: Sanofi R&D, Lead Generation, Chilly-Mazarin, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Slowinski
authors.affiliation: Sanofi R&D, Translational Sciences Unit, Chilly-Mazarin, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Vigé
authors.affiliation: Sanofi R&D, Translational Sciences Unit, Chilly-Mazarin, France.
authors.forename: Olivier E
authors.initials: OE
authors.lastname: Bergis
authors.affiliation: Sanofi R&D, 1041 Route 202/206, Bridgewater, NJ, USA.
authors.forename: Rosy
authors.initials: R
authors.lastname: Sher
authors.affiliation: Sanofi R&D, 1041 Route 202/206, Bridgewater, NJ, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Kosley
authors.affiliation: Sanofi R&D, 1041 Route 202/206, Bridgewater, NJ, USA.
authors.forename: Sathapana
authors.initials: S
authors.lastname: Kongsamut
authors.affiliation: Sanofi R&D, 1041 Route 202/206, Bridgewater, NJ, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Black
authors.affiliation: Sanofi R&D, 1041 Route 202/206, Bridgewater, NJ, USA.
authors.forename: Geoffrey B
authors.initials: GB
authors.lastname: Varty
mesh_terms: D000495:Allosteric Site; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001288:Attention / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy*; D000242:Cyclic AMP / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000737:chemistry / Q000494:pharmacology; D004565:Electroconvulsive Therapy; D057809:HEK293 Cells; D006801:Humans; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000187:drug effects*; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D010641:Phenotype; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000737:chemistry*; D012559:Schizophrenia / Q000188:drug therapy*
chemical_list: D000662:Amphetamines; D007189:Indans; D010080:Oxazoles; D011743:Pyrimidines; D018091:Receptors, AMPA; C000627704:SAR218645; D016291:Dizocilpine Maleate; D000242:Cyclic AMP; C104722:glutamate receptor ionotropic, AMPA 2; D002118:Calcium