Synthesis and Characterization of Novel Acyl-Glycine Inhibitors of GlyT2

Mostyn, Shannon N.; Carland, Jane E.; Shimmon, Susan; Ryan, Renae M.; Rawling, Tristan; Vandenberg, Robert J.

doi:10.1021/acschemneuro.7b00105

Cited by 31 publications

(60 citation statements)

References 41 publications

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“…Unfavorable pharmacokinetic properties of these GlyT2 inhibitors, however, prevented a clinical application. Future studies, analyzing the in vivo properties of newly developed GlyT2 inhibitors ( Mingorance-Le Meur et al, 2013 ; Mostyn et al, 2017 ) might revive the interest in GlyT2 inhibitors for the treatment of chronic pain in the future.…”

Section: Discussionmentioning

confidence: 99%

The GlyT1 Inhibitor Bitopertin Ameliorates Allodynia and Hyperalgesia in Animal Models of Neuropathic and Inflammatory Pain

Armbruster¹,

Neumann²,

Kötter³

et al. 2018

Front. Mol. Neurosci.

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Background: Chronic pain conditions are difficult to treat and the therapeutic outcome is frequently unsatisfactory. Changes in excitation/inhibition balance within the dorsal horn contribute to the establishment and persistence of chronic pain. Thus, facilitation of inhibitory neurotransmission is a promising approach to treat chronic pain pharmacologically. Glycine transporter 1 (GlyT1) plays an important role in regulating extracellular glycine concentrations. Aim of the present study therefore was to investigate whether the specific GlyT1 inhibitor bitopertin (RG1678; RO4917838) might constitute a novel treatment for chronic pain by facilitating glycinergic inhibition.Methods: Mechanical allodynia and thermal hyperalgesia were induced by chronic constriction injury of the sciatic nerve or carrageenan injections into the plantar surface of the hind paw in rodents. The effect of acute and long-term bitopertin application on the reaction threshold to mechanical and thermal stimuli was determined. General activity was determined in open field experiments. The glycine concentration in cerebrospinal fluid and blood was measured by HPLC.Results: Systemic application of bitopertin in chronic pain conditions lead to a significant increase of the reaction thresholds to mechanical and thermal stimuli in a time and dose-dependent manner. Long-term application of bitopertin effectuated stable beneficial effects over 4 weeks. Bitopertin did not alter reaction thresholds to stimuli in control animals and had no effect on general locomotor activity and anxiety but lead to an increased glycine concentration in cerebrospinal fluid.Conclusion: These findings suggest that inhibition of the GlyT1 by bitopertin represents a promising new approach for the treatment of chronic pain.

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Section: Discussionmentioning

confidence: 99%

The GlyT1 Inhibitor Bitopertin Ameliorates Allodynia and Hyperalgesia in Animal Models of Neuropathic and Inflammatory Pain

Armbruster¹,

Neumann²,

Kötter³

et al. 2018

Front. Mol. Neurosci.

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“…We have previously found that these compounds have no detectable effect on GlyT1 expressed in oocytes (Mostyn et al ., ; Table ). To rule out any alternative modes of action, including activity at the glycine receptor, we performed occlusion experiments in lamina II neurons where slices were incubated with the GlyT2 inhibitor ORG25543 prior and during application of NOGly (Figure ).…”

Section: Resultsmentioning

confidence: 95%

“…The aim of this study was to investigate the effect of lipid inhibitors of GlyT2 on synaptic transmission at inhibitory and excitatory synapses within the dorsal horn. Oocyte studies show similar GlyT2 IC 50 values for the four compounds tested, which range from 0.32 to 0.81 μM (Wiles et al ., ; Carland et al ., ; Mostyn et al ., ). In the dorsal horn, all compounds also had similar effects on glycinergic transmission, which is likely to be due to the small differences in GlyT2 IC 50 .…”

Section: Discussionmentioning

confidence: 97%

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Activity of novel lipid glycine transporter inhibitors on synaptic signalling in the dorsal horn of the spinal cord

Winters

Rawling

Vandenberg

et al. 2018

British J Pharmacology

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“…The effects of the GlyT2 specific inhibitor, C18-cis-ω9-L-methionine [17], the GlyR specific PAM, C18-cis-ω7-glycine [18] and the dual action modulator C18-cis-ω9-glycine [17,18] were assessed in co-expressed GlyRα1/GlyT2 cells. As the data previously collected on the activity of these lipids at GlyRα1 was measured using a 1 µM concentration [18] all the following experiments have also been conducted using a 1 µM concentration.…”

Section: Novel Bioactive Lipid Modulators Of Glyrα1 and Glyt2mentioning

confidence: 99%

A System for Assessing Dual Action Modulators of Glycine Transporters and Glycine Receptors

Sheipouri¹,

Gallagher²,

Shimmon³

et al. 2020

Preprint

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Reduced inhibitory glycinergic neurotransmission is implicated in a number of neurological conditions such as neuropathic pain, schizophrenia, epilepsy and hyperekplexia. Restoring glycinergic signalling may be an effective method of treating these pathologies. Glycine transporters (GlyTs) control synaptic and extra-synaptic glycine concentrations and slowing the reuptake of glycine using specific GlyT inhibitors will increase glycine extracellular concentrations and increase glycine receptor (GlyR) activation. Glycinergic neurotransmission can also be improved through positive allosteric modulation (PAM) of GlyRs. Despite efforts to manipulate this synapse, no therapeutics currently target it. We propose that dual action modulators of both GlyTs and GlyRs may show greater therapeutic potential than those targeting individual proteins. To show this, we have characterized a co-expression system in Xenopus laevis oocytes consisting of GlyT1 or GlyT2 co-expressed with GlyRα1. We use two electrode voltage clamp recording techniques to measure the impact of GlyTs on GlyRs and the effects of modulators of these proteins. We show that increases in GlyT density in close proximity to GlyRs diminish receptor currents. Reductions in GlyR mediated currents are not observed when non-transportable GlyR agonists are applied or when Na+ is not available. GlyTs reduce glycine concentrations across different concentration ranges, corresponding with their ion-coupling stoichiometry, and full receptor currents can be restored when GlyTs are blocked with selective inhibitors. We show that partial inhibition of GlyT2 and modest GlyRα1 potentiation using a dual action compound, is as useful in restoring GlyR currents as a full and potent single target GlyT2 inhibitor or single target GlyRα1 PAM.

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Synthesis and Characterization of Novel Acyl-Glycine Inhibitors of GlyT2

Cited by 31 publications

References 41 publications

The GlyT1 Inhibitor Bitopertin Ameliorates Allodynia and Hyperalgesia in Animal Models of Neuropathic and Inflammatory Pain

The GlyT1 Inhibitor Bitopertin Ameliorates Allodynia and Hyperalgesia in Animal Models of Neuropathic and Inflammatory Pain

Activity of novel lipid glycine transporter inhibitors on synaptic signalling in the dorsal horn of the spinal cord

A System for Assessing Dual Action Modulators of Glycine Transporters and Glycine Receptors

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