title: Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic.
abstract: Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC50=18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID50: 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 microM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB1 receptors): it reversed the decrease in electrically evoked [3H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.
authors.affiliation: CNS Department, Sanofi-Synthelabo Recherche, Bagneux, France. Ronan.Depoortere@Sanofi-Synthelabo.com
authors.forename: Ronan
authors.initials: R
authors.lastname: Depoortère
authors.forename: Gihad
authors.initials: G
authors.lastname: Dargazanli
authors.forename: Genevieve
authors.initials: G
authors.lastname: Estenne-Bouhtou
authors.forename: Annick
authors.initials: A
authors.lastname: Coste
authors.forename: Christophe
authors.initials: C
authors.lastname: Lanneau
authors.forename: Christophe
authors.initials: C
authors.lastname: Desvignes
authors.forename: Martine
authors.initials: M
authors.lastname: Poncelet
authors.forename: Michel
authors.initials: M
authors.lastname: Heaulme
authors.forename: Vincent
authors.initials: V
authors.lastname: Santucci
authors.forename: Michel
authors.initials: M
authors.lastname: Decobert
authors.forename: Annie
authors.initials: A
authors.lastname: Cudennec
authors.forename: Carolle
authors.initials: C
authors.lastname: Voltz
authors.forename: Denis
authors.initials: D
authors.lastname: Boulay
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Terranova
authors.forename: Jeanne
authors.initials: J
authors.lastname: Stemmelin
authors.forename: Pierre
authors.initials: P
authors.lastname: Roger
authors.forename: Benoit
authors.initials: B
authors.lastname: Marabout
authors.forename: Mireille
authors.initials: M
authors.lastname: Sevrin
authors.forename: Xavier
authors.initials: X
authors.lastname: Vigé
authors.forename: Bruno
authors.initials: B
authors.lastname: Biton
authors.forename: Régis
authors.initials: R
authors.lastname: Steinberg
authors.forename: Dominique
authors.initials: D
authors.lastname: Françon
authors.forename: Richard
authors.initials: R
authors.lastname: Alonso
authors.forename: Patrick
authors.initials: P
authors.lastname: Avenet
authors.forename: Florence
authors.initials: F
authors.lastname: Oury-Donat
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Perrault
authors.forename: Guy
authors.initials: G
authors.lastname: Griebel
authors.forename: Pascal
authors.initials: P
authors.lastname: George
authors.forename: Philippe
authors.initials: P
authors.lastname: Soubrié
authors.forename: Bernard
authors.initials: B
authors.lastname: Scatton
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects; D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects*; D002247:Carbon Isotopes / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002940:Circadian Rhythm / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D005998:Glycine / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects
chemical_list: C507205:2-chloro-N-((S)-phenyl((2S)-piperidin-2-yl)methyl)-3-trifluoromethyl benzamide; D001549:Benzamides; D002247:Carbon Isotopes; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D050487:Glycine Plasma Membrane Transport Proteins; D010880:Piperidines; D000661:Amphetamine; D000109:Acetylcholine; D005998:Glycine