P.3.e.009 Glycine reuptake inhibitor RG1678: results of the proof-of-concept study for the treatment of negative symptoms in schizophrenia

Umbricht, Daniel; Martin‐Facklam, Meret; Youssef, Eman; Yoo, KyoSang; Dorflinger, Ernest; Bausch, Alexander; Alberati, Daniela; Santarelli, L.

doi:10.1016/s0924-977x(11)70841-0

Cited by 18 publications

(26 citation statements)

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“…PANSS negative symptom subscale scores were lower on the active vs the placebo Org 25935 condition, but the differences were not statistically significant. The lack of statistically significant effects of Org 25935 on ketamine-induced negative symptoms in healthy subjects contrasts with a recent report that the addition of RG1678, a GlyT1 inhibitor, to atypical antipsychotic treatment resulted in an improvement of negative symptoms in schizophrenia patients (Umbricht, 2010). However, it should be noted that there are important differences in the design (single dose vs multiple chronic dosing), samples (healthy volunteers vs schizophrenia patients), and target (ketamine-induced symptoms vs schizophrenia-related negative symptoms) between the studies.…”

Section: Gly Transporter Inhibitor Interactions With Ketaminecontrasting

confidence: 90%

“…While Org 25935 is procognitive in several animal models of cognition such as the NOR, there appears to be an inverse dose-response where robust effects were seen at lower doses, but this response was abolished at higher doses (Snigdha et al, 2007). Similarly, in the recent clinical trial with RG1678, a loss of efficacy was observed at higher doses (Umbricht, 2010). Furthermore, preclinical studies suggest that partial (50%) occupancy of brain GlyT1 is necessary to obtain efficacy in behavioral models relevant to schizophrenia (Alberati et al, 2011).…”

Section: Gly Transporter Inhibitor Interactions With Ketaminementioning

confidence: 95%

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Glycine Transporter Inhibitor Attenuates the Psychotomimetic Effects of Ketamine in Healthy Males: Preliminary Evidence

D’Souza

Singh

Elander

et al. 2011

Neuropsychopharmacol

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Enhancing glutamate function by stimulating the glycine site of the NMDA receptor with glycine, D-serine, or with drugs that inhibit glycine reuptake may have therapeutic potential in schizophrenia. The effects of a single oral dose of cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) amino-methylcarboxylic acid hydrochloride (Org 25935), a glycine transporter-1 (GlyT1) inhibitor, and placebo pretreatment on ketamine-induced schizophrenia-like psychotic symptoms, perceptual alterations, and subjective effects were evaluated in 12 healthy male subjects in a randomized, counter-balanced, within-subjects, crossover design. At 2.5 h after administration of the Org 25935 or placebo, subjects received a ketamine bolus and constant infusion lasting 100 min. Psychotic symptoms, perceptual, and a number of subjective effects were assessed repeatedly before, several times during, and after completion of ketamine administration. A cognitive battery was administered once per test day. Ketamine produced behavioral, subjective, and cognitive effects consistent with its known effects. Org 25935 reduced the ketamine-induced increases in measures of psychosis (Positive and Negative Syndrome Scale (PANSS)) and perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)). The magnitude of the effect of Org 25935 on ketamine-induced increases in Total PANSS and CADSS Clinician-rated scores was 0.71 and 0.98 (SD units), respectively. None of the behavioral effects of ketamine were increased by Org 25935 pretreatment. Org 25935 worsened some aspects of learning and delayed recall, and trended to improve choice reaction time. This study demonstrates for the first time in humans that a GlyT1 inhibitor reduces the effects induced by NMDA receptor antagonism. These findings provide preliminary support for further study of the antipsychotic potential of GlyT1 inhibitors.

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Section: Gly Transporter Inhibitor Interactions With Ketaminecontrasting

confidence: 90%

Section: Gly Transporter Inhibitor Interactions With Ketaminementioning

confidence: 95%

Glycine Transporter Inhibitor Attenuates the Psychotomimetic Effects of Ketamine in Healthy Males: Preliminary Evidence

D’Souza

Singh

Elander

et al. 2011

Neuropsychopharmacol

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“…GlyT1 occupancy associated with beneficial treatment response was in the range of 30%-50%, with loss of efficacy at higher occupancies suggesting a critical therapeutic window and a need for careful dose selection in phase 2 studies (Umbricht et al, unpublished data). 64 If confirmed in ongoing phase 3 studies, this will be the first compound developed specifically for treatment of schizophrenia based on PCP/NMDA models.…”

Section: Treatment Implicationsmentioning

confidence: 91%

Has an Angel Shown the Way? Etiological and Therapeutic Implications of the PCP/NMDA Model of Schizophrenia

Javitt

Zukin²,

Heresco-Levy

et al. 2012

Schizophrenia Bulletin

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280

203

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“…23 The first successful and promising application of this approach through a mechanism also aimed at enhancing NMDA receptor function was recently validated clinically in a small patient population using the GlyT1 inhibitor RG1678, demonstrating for the first time statistically significant effects in treating the negative symptoms of the disease. 24 In the case of mGlu 5 , the rationale and interest in pursuing mGlu 5 as a novel target for the treatment of schizophrenia continues to show great promise and has been bolstered recently by several pro-cognitive studies reported using novel chemotypes (vide infra). Elegant reviews which outline the detailed genetic and pharmacological evolution of the supporting rationale for the role mGlu 5 as it relates to NMDA mediated circuitry and potential therapeutic benefit in schizophrenia are noted.…”

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confidence: 99%

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

Stauffer

2011

ACS Chem. Neurosci.

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ABSTRACT:This Review describes recent trends in the development of small molecule mGlu 5 positive allosteric modulators (PAMs). A large body of pharmacological, genetic, electrophysiological, and in vivo behavioral evidence has accumulated over the past decade which continues to support the hypothesis and rationale for the activation of the metabotropic glutamate receptor subtype 5 (mGlu 5 ) as a viable and promising target for the development of novel antipsychotics. Until recently, functionally efficacious and potent mGlu 5 PAMs have been somewhat structurally limited in scope and slow to emerge. This Review will discuss efforts since late 2008 which have provided novel mGlu 5 PAM chemotypes, offering ligands with a diverse range of pharmacological, physicochemical, and DMPK properties that were previously unavailable. In addition, significant biological studies of importance in the past few years using the well established PAMs known as DFB, CPPHA, CDPPB, and ADX-47273 will be discussed. KEYWORDS:Metabotropic, mGlu 5 , schizophrenia, allosteric, positive allosteric modulator, DFB, CPPHA, CDPPB, ADX-47273, glutamate G lutamate is the single most important excitatory neurotransmitter in the mammalian central nervous system (CNS). 1 The concentration of glutamate within the cytoplasm of glutamatergic neurons is several times more than that of any other amino acid, approximately 5À10 mM, and within synaptic vesicles glutamate reserves can be significantly higher. The two major receptor classes that are known to be modulated by glutamate include ionotropic glutamate receptors (iGlus), which are multimeric glutamate-gated cation channels, and metabotropic glutamate receptors (mGlus), which are seven transmembrane heptahelical (7TM) spanning proteins coupled to effector G-proteins. 2 Ionotropic glutamate receptors are responsible for fast acting glutaminergic transmission in the CNS and are mediated by the three subclasses of iGlus: the R-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors. All three iGlu channels undergo a conformational change and open in response to glutamate binding and induce excitatory post synaptic current, with the NMDA receptor perhaps best characterized and central to many hypotheses of CNS pathologies. A wide range of neurological disorders including chronic pain, schizophrenia, Alzheimer's disease, epilepsy, drug addiction, and fragile X syndrome have been associated with dysfunction of glutamatergic systems. 1,3 In contrast to ionotropic glutamate receptors, metabotropic glutamate receptors bind glutamate to modulate either presynaptic neurotransmitter release or postsynaptic excitatory neurotransmission.Allosteric modulation of metabotropic glutamate receptors as a glutamate-based approach for therapeutic intervention, either via enhancing or inhibiting endogenous agonist responses, is a highly active area of research and drug development. 3À7 Allosteric mechanisms of receptor modulation provide several potential advantages o...

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P.3.e.009 Glycine reuptake inhibitor RG1678: results of the proof-of-concept study for the treatment of negative symptoms in schizophrenia

Cited by 18 publications

References 0 publications

Glycine Transporter Inhibitor Attenuates the Psychotomimetic Effects of Ketamine in Healthy Males: Preliminary Evidence

Glycine Transporter Inhibitor Attenuates the Psychotomimetic Effects of Ketamine in Healthy Males: Preliminary Evidence

Has an Angel Shown the Way? Etiological and Therapeutic Implications of the PCP/NMDA Model of Schizophrenia

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

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P.3.e.009 Glycine reuptake inhibitor RG1678: results of the proof-of-concept study for the treatment of negative symptoms in schizophrenia

Cited by 18 publications

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Glycine Transporter Inhibitor Attenuates the Psychotomimetic Effects of Ketamine in Healthy Males: Preliminary Evidence

Glycine Transporter Inhibitor Attenuates the Psychotomimetic Effects of Ketamine in Healthy Males: Preliminary Evidence

Has an Angel Shown the Way? Etiological and Therapeutic Implications of the PCP/NMDA Model of Schizophrenia

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu5)

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Product

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Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)