Relief of Cancer Pain by Glycine Transporter Inhibitors

Motoyama, Naoyo; Morita, Kenichi; Shiraishi, Seiji; Kitayama, Tomoya; Kanematsu, Takashi; Uezono, Yasuhito; Dohi, Toshihiro

doi:10.1213/ane.0000000000000388

Cited by 18 publications

(30 citation statements)

References 34 publications

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“…However, at high concentrations ORG25543 was toxic and produced motor dysfunction, convulsions and spams [ 81 ]. Interestingly, lower affinity derivatives of ORG25543 seem to keep its efficacy as analgesic compounds without toxicity [ 81 , 82 ]. Recently, the phenoxymethylbenzamide compound GT-0198, a structurally novel and orally adminstrable GlyT2 inhibitor with excellent brain penetrance, showed a potent analgesic effect in the partial sciatic nerve ligation model of neuropathic pain, without side motor effects [ 83 ].…”

Section: Glyt2 In Neuronal Pathologiesmentioning

confidence: 99%

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

2016

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Glycinergic neurons are major contributors to the regulation of neuronal excitability, mainly in caudal areas of the nervous system. These neurons control fluxes of sensory information between the periphery and the CNS and diverse motor activities like locomotion, respiration or vocalization. The phenotype of a glycinergic neuron is determined by the expression of at least two proteins: GlyT2, a plasma membrane transporter of glycine, and VIAAT, a vesicular transporter shared by glycine and GABA. In this article, we review recent advances in understanding the role of GlyT2 in the pathophysiology of inhibitory glycinergic neurotransmission. GlyT2 mutations are associated to decreased glycinergic function that results in a rare movement disease termed hyperekplexia (HPX) or startle disease. In addition, glycinergic neurons control pain transmission in the dorsal spinal cord and their function is reduced in chronic pain states. A moderate inhibition of GlyT2 may potentiate glycinergic inhibition and constitutes an attractive target for pharmacological intervention against these devastating conditions.

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Section: Glyt2 In Neuronal Pathologiesmentioning

confidence: 99%

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

2016

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“…For example, a recent report showed that oral or IV administration of GlyT1 inhibitor drastically improved pain-like behavior in a mouse femur bone cancer model. Authors concluded that GlyT inhibitors can provide a new path toward the treatment of bone cancer pain with morphine or alone ( Motoyama et al, 2014 ). No specific role for GlyT1 has been previously reported for hematological malignancies.…”

Section: Slc6a9 Sodium- and Chloride-dependent Glycine Transporter 1mentioning

confidence: 99%

Does aberrant membrane transport contribute to poor outcome in adult acute myeloid leukemia?

Chigaev

2015

Front. Pharmacol.

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Acute myeloid leukemia in adults is a highly heterogeneous disease. Gene expression profiling performed using unsupervised algorithms can be used to distinguish specific groups of patients within a large patient cohort. The identified gene expression signatures can offer insights into underlying physiological mechanisms of disease pathogenesis. Here, the analysis of several related gene expression clusters associated with poor outcome, worst overall survival and highest rates of resistant disease and obtained from the patients at the time of diagnosis or from previously untreated individuals is presented. Surprisingly, these gene clusters appear to be enriched for genes corresponding to proteins involved in transport across membranes (transporters, carriers and channels). Several ideas describing the possible relationship of membrane transport activity and leukemic cell biology, including the “Warburg effect,” the specific role of chloride ion transport, direct “import” of metabolic energy through uptake of creatine phosphate, and modification of the bone marrow niche microenvironment are discussed.

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“…By increasing glycine concentration in the synaptic cleft and thus glycinergic neurotransmission, GlyT2 inhibition can be expected to be active against pain, which could be demonstrated in animal models. Org25543 (Figure 1; 2 ) and ALX1393 (Figure 1; 3 ) represent the two so far best characterized GlyT2 inhibitors, which were shown to be able to reduce allodynia in animals due to their ability to inhibit the glycine transport into the presynaptic neuron [7–10] . Unfortunately, both compounds exhibit considerable disadvantages.…”

Section: Introductionmentioning

confidence: 99%

MS Binding Assays for Glycine Transporter 2 (GlyT2) Employing Org25543 as Reporter Ligand

et al. 2020

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This study describes the first binding assay for glycine transporter 2 (GlyT2) following the concept of MS Binding Assays. The selective GlyT2 inhibitor Org25543 was employed as a reporter ligand and it was quantified with a highly sensitive and rapid LC‐ESI‐MS/MS method. Binding of Org25543 at GlyT2 was characterized in kinetic and saturation experiments with an off‐rate of 7.07×10−3 s−1, an on‐rate of 1.01×106 M−1 s−1, and an equilibrium dissociation constant of 7.45 nM. Furthermore, the inhibitory constants of 19 GlyT ligands were determined in competition experiments. The validity of the GlyT2 affinities determined with the binding assay was examined by a comparison with published inhibitory potencies from various functional assays. With the capability for affinity determination towards GlyT2 the developed MS Binding Assays provide the first tool for affinity profiling of potential ligands and it represents a valuable new alternative to functional assays addressing GlyT2.

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Relief of Cancer Pain by Glycine Transporter Inhibitors

Abstract: GlyT inhibitors with or without morphine may be a new strategy for the treatment of bone cancer pain and lead to further investigations of the mechanisms underlying the development of bone cancer pain.

Cited by 18 publications

References 34 publications

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

Does aberrant membrane transport contribute to poor outcome in adult acute myeloid leukemia?

MS Binding Assays for Glycine Transporter 2 (GlyT2) Employing Org25543 as Reporter Ligand

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