Glycine reuptake inhibitor RG1678: A pharmacologic characterization of an investigational agent for the treatment of schizophrenia

Alberati, Daniela; Moreau, Jean‐Luc; Lengyel, Judith A.; Hauser, Nicole; Mory, Roland; Borroni, Edilio; Pinard, Emmanuel; Knoflach, Frédéric; Schlotterbeck, Götz; Hainzl, Dominik; Wettstein, Joseph G.

doi:10.1016/j.neuropharm.2011.11.008

Cited by 123 publications

(88 citation statements)

References 57 publications

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“…GlyT-1 inhibitors are effective in most rodent models of schizophrenia associated with alterations in NMDA transmission (Alberati et al, 2011;Boulay et al, 2010;Yang et al, 2010). GlyT-1 inhibitors have also been reported to alleviate some of the ketamine-induced behavioural and cognitive disturbances in nonhuman primates (Roberts et al, 2010b) and in humans (D'Souza et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Relationship Between Glycine Transporter 1 Inhibition as Measured with Positron Emission Tomography and Changes in Cognitive Performances in Nonhuman Primates

Castner

Murthy

Ridler

et al. 2014

Neuropsychopharmacol

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Several lines of evidence suggest that schizophrenia is associated with deficits in glutamatergic transmission at the N-methyl-D-aspartate (NMDA) receptors. Glycine is a NMDA receptor co-agonist, and extracellular levels of glycine are regulated in the forebrain by the glycine type-1 transporters (GlyT-1). GlyT-1 inhibitors elevate extracellular glycine and thus potentiate NMDA transmission. This mechanism represents a promising new avenue for the treatment of schizophrenia. Here, the recently introduced positron emission tomography radiotracer [11C]GSK931145 was used to quantify the relationship between occupancy of GlyT-1 by a GlyT-1 inhibitor, Org 25935, and its impact on spatial working memory performances in rhesus monkeys. The effect of Org 25935 on working memory was assessed both in control conditions and during a state of relative NMDA hypofunction induced by ketamine administration, at a dose selected for each animal to reduce task performance by about 50%. Under control conditions, Org 25935 had no effect on working memory at GlyT-1 occupancies lower than 75% and significantly impaired working memory at occupancies higher than 75%. Under ketamine conditions, Org 25935 reversed the deficit in working memory induced by ketamine and did so optimally in the 40-70% GlyT-1 occupancy range. The results confirm the efficacy of this mechanism to correct working memory deficits associated with NMDA hypofunction. These data also suggest the existence of an inverted-U dose-response curve in the potential therapeutic effect of this class of compounds.

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Section: Introductionmentioning

confidence: 99%

Relationship Between Glycine Transporter 1 Inhibition as Measured with Positron Emission Tomography and Changes in Cognitive Performances in Nonhuman Primates

Castner

Murthy

Ridler

et al. 2014

Neuropsychopharmacol

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“…Because TCN 201 is reported to be a negative allostereic modulator of glycine binding in GluN1/2A receptors (Edman et al, 2012;Hansen et al, 2012), we examined it in the presence of bitopertin, a glycine uptake inhibitor. It has been reported that 100 nM, but not 300 nM, bitopertin facilitates LTP induction in rat slices (Alberati et al, 2012). Administration of 30 nM bitopertin augmented NMDAR EPSPs (153 6 24%, N 5 5; Fig.…”

Section: Resultsmentioning

confidence: 71%

Sensitivity of N-Methyl-d-Aspartate Receptor–Mediated Excitatory Postsynaptic Potentials and Synaptic Plasticity to TCN 201 and TCN 213 in Rat Hippocampal Slices

Izumi¹,

Zorumski²

2014

J Pharmacol Exp Ther

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Whereas ifenprodil has been used as a selective GluN1/GluN2B (NR1/NR2B, B-type) receptor antagonist to distinguish between GluN2B (NR2B) and GluN2A (NR2A)-containing N-methyl-Daspartate receptors (NMDARs), Contrary to this prediction, inhibition of NMDAR EPSPs by the TCN compounds and ifenprodil were largely overlapping in the CA1 region of hippocampal slices from 30-day-old rats. After partial inhibition by ifenprodil, TCN compounds produced little further suppression of NMDAR EPSPs. Similarly, after partial inhibition by TCN compounds ifenprodil failed to further suppress NMDAR EPSPs. However, low micromolar D-2-amino-5-phosphonovalerate, a competitive NMDAR antagonist, which alone only partially inhibits NMDAR EPSPs, markedly suppresses residual NMDAR responses in the presence of ifenprodil or the TCNs, suggesting that low 2-amino-5-phosphonovalerate antagonizes both ifenprodil-and TCN-insensitive synaptic NMDARs. These observations can be most readily interpreted if ifenprodil and TCNs act on a similar population of synaptic NMDARs. Recent lines of evidence suggest that the majority of hippocampal synaptic NMDARs are triheteromers. If so, modulation of GluN2A, and not just GluN2B NMDARs, could dampen long-term depression (LTD). Indeed, both TCNs, like ifenprodil, blocked LTD, suggesting the involvement of ifenprodil-and TCN-sensitive NMDARs in LTD induction. However, the TCNs plus ifenprodil failed to inhibit long-term potentiation (LTP), suggesting that neither ifenprodil-nor TCN-sensitive NMDARs are essential for LTP induction.

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“…Bitopertin has demonstrated efficacy in preclinical assays of decreased NMDA receptor functioning and models of schizophrenia. In addition, it increases cerebrospinal fluid (CSF) glycine levels in a dose-dependent manner (Alberati et al, 2012). Correspondingly, in a proof-of-mechanism study in healthy volunteers, once-daily oral doses of 3-60 mg bitopertin over 10 days resulted in a dose-dependent increase in glycine levels in CSF of a similar magnitude .…”

Section: Introductionmentioning

confidence: 88%

“…Indeed GlyT1 has been found to be expressed not only in glial cells but also in neurons, particularly in glutamatergic neurons of cortex and hippocampus, whereas in more caudal brain regions it is predominantly expressed in glial cells surrounding glutamatergic synapses (Smith et al, 1992;Cubelos et al, 2005). In addition, the increased levels of extracellular glycine in rat striatum induced by bitopertin, as measured by microdialysis (Alberati et al, 2012), were similar to those reported for SSR504734, another GRI, where the microdialysis probe was implanted in medial prefrontal cortex (Depoortère et al, 2005). Figure 3 Relationship between bitopertin pre-and post-scan mean plasma concentration and GlyT1 occupancy in healthy volunteers on last day of treatment in the (a) cerebellum, (b) pons, and (c) thalamus, derived by two-tissue five-parameter (2T5P) model, simplified reference tissue model (SRTM), and pseudoreference tissue model (PRTM) as well as (d) on last day of treatment and 2 days after drug discontinuation in the thalamus.…”

Section: Selection Of Reference Regionmentioning

confidence: 99%

Glycine Transporter Type 1 Occupancy by Bitopertin: a Positron Emission Tomography Study in Healthy Volunteers

Martin‐Facklam

Pizzagalli

Zhou

et al. 2012

Neuropsychopharmacol

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Deficient N-methyl-D-aspartate (NMDA) receptor transmission is thought to underlie schizophrenia. An approach for normalizing glutamate neurotransmission by enhancing NMDA receptor transmission is to increase glycine availability by inhibiting the glycine transporter type 1 (GlyT1). This study investigated the relationship between the plasma concentration of the glycine reuptake inhibitor bitopertin (RG1678) and brain GlyT1 occupancy. Healthy male volunteers received up to 175 mg bitopertin once daily, for 10-12 days. Three positron emission tomography scans, preceded by a single intravenous infusion of B30 mCi [ 11 C]RO5013853, were performed: at baseline, on the last day of bitopertin treatment, and 2 days after drug discontinuation. Eighteen subjects were enrolled. At baseline, regional volume of distribution (V T ) values were highest in the pons, thalamus, and cerebellum (1.7-2.7 ml/cm 3 ) and lowest in cortical areas (B0.8 ml/cm 3 ). V T values were reduced to a homogeneous level following administration of 175 mg bitopertin. Occupancy values derived by a two-tissue five-parameter (2T5P) model, a simplified reference tissue model (SRTM), and a pseudoreference tissue model (PRTM) were overall comparable. At steady state, the relationship between bitopertin plasma concentration and GlyT1 occupancy derived by the 2T5P model, SRTM, and PRTM exhibited an EC 50 of B190, B200, and B130 ng/ml, respectively. E max was B92% independently of the model used. Bitopertin plasma concentration was a reliable predictor of occupancy because the concentrationoccupancy relationship was superimposable at steady state and 2 days after drug discontinuation. These data allow understanding of the concentration-occupancy-efficacy relationship of bitopertin and support dose selection of future molecules.

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Glycine reuptake inhibitor RG1678: A pharmacologic characterization of an investigational agent for the treatment of schizophrenia

Cited by 123 publications

References 57 publications

Relationship Between Glycine Transporter 1 Inhibition as Measured with Positron Emission Tomography and Changes in Cognitive Performances in Nonhuman Primates

Relationship Between Glycine Transporter 1 Inhibition as Measured with Positron Emission Tomography and Changes in Cognitive Performances in Nonhuman Primates

Sensitivity of N-Methyl-d-Aspartate Receptor–Mediated Excitatory Postsynaptic Potentials and Synaptic Plasticity to TCN 201 and TCN 213 in Rat Hippocampal Slices

Glycine Transporter Type 1 Occupancy by Bitopertin: a Positron Emission Tomography Study in Healthy Volunteers

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