GlyT-1 Inhibitors: From Hits to Clinical Candidates

Porter, Roderick A.; Dawson, Lee A.

doi:10.1007/7355_2014_53

Cited by 14 publications

(15 citation statements)

References 165 publications

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“…Among several GlyT1 inhibitors that have undergone clinical trials, bitopertin has seen the most success by advancing to phase III trials for the treatment of schizophrenia2627. ALX, on the other hand, has demonstrated relatively poorer tolerance in vivo 48.…”

Section: Discussionmentioning

confidence: 99%

“…Modulation of NMDA receptor neurotransmission is currently used as a therapy for schizophrenia, a disease that displays reduced NMDA receptor function. In fact, the clinical trials have shown that augmentation of NMDA receptor function via GlyT1 inhibitors improve symptoms of schizophrenia2627. However, no studies to date have investigated the therapeutic potential of GlyT1 inhibition for the treatment of diabetes and obesity.…”

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confidence: 99%

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Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity

et al. 2016

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Impaired glucose homeostasis and energy balance are integral to the pathophysiology of diabetes and obesity. Here we show that administration of a glycine transporter 1 (GlyT1) inhibitor, or molecular GlyT1 knockdown, in the dorsal vagal complex (DVC) suppresses glucose production, increases glucose tolerance and reduces food intake and body weight gain in healthy, obese and diabetic rats. These findings provide proof of concept that GlyT1 inhibition in the brain improves glucose and energy homeostasis. Considering the clinical safety and efficacy of GlyT1 inhibitors in raising glycine levels in clinical trials for schizophrenia, we propose that GlyT1 inhibitors have the potential to be repurposed as a treatment of both obesity and diabetes.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity

et al. 2016

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“…SLC6A9 controls NMDA activity by mediating the clearance of glycine from excitatory synapses. Inhibition of SLC6A9 leads to NMDA activation and cognition enhancement in mouse schizophrenia models, although clinical development of SLC6A9 inhibitors has been unsatisfactory …”

Section: Slcs In Human Diseasementioning

confidence: 99%

The Druggability of Solute Carriers

et al. 2019

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The transport of materials across membranes is a vital process for all aspects of cellular function, including growth, metabolism, and communication. Protein transporters are the molecular gates that control this movement and serve as key points of regulation for these processes, thus representing an attractive class of therapeutic targets. With more than 400 members, the solute carrier (SLC) membrane transport proteins are the largest family of transporters, yet, they are pharmacologically underexploited relative to other protein families and many of the available chemical tools possess suboptimal selectivity and efficacy. Fortuitously, there is increased interest in elucidating the physiological roles of SLCs as well as growing recognition of their therapeutic potential. This Perspective provides an overview of the SLC superfamily, including their biochemical and functional features, as well as their roles in various human diseases. In particular, we explore efforts and associated challenges toward drugging SLCs, as well as highlight opportunities for future drug discovery.

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“…The tripartite interaction between purinergic modulation, glutamatergic-glycinergic neurotransmission, and microglia activation provides three therapeutic target pathways in neuroinflammatory-neurodegenerative disorders of the retina. First, GlyT-1 inhibitors [16,113] block reverse-mode operation of the transporter in pathological conditions and decrease the concentrations of the coagonist glycine at NR1/NR2B-type NMDA receptors. These effects of GlyT-1 inhibitors may lead to protection of retina ganglion cells.…”

Section: Conclusion: Possible Therapeutic Consequencesmentioning

confidence: 99%

Purinergic–Glycinergic Interaction in Neurodegenerative and Neuroinflammatory Disorders of the Retina

Hársing

Szénási

Zelles

et al. 2021

IJMS

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Neurodegenerative–neuroinflammatory disorders of the retina seriously hamper human vision. In searching for key factors that contribute to the development of these pathologies, we considered potential interactions among purinergic neuromodulation, glycinergic neurotransmission, and microglia activity in the retina. Energy deprivation at cellular levels is mainly due to impaired blood circulation leading to increased release of ATP and adenosine as well as glutamate and glycine. Interactions between these modulators and neurotransmitters are manifold. First, P2Y purinoceptor agonists facilitate reuptake of glycine by glycine transporter 1, while its inhibitors reduce reverse-mode operation; these events may lower extracellular glycine levels. The consequential changes in extracellular glycine concentration can lead to parallel changes in the activity of NR1/NR2B type NMDA receptors of which glycine is a mandatory agonist, and thereby may reduce neurodegenerative events in the retina. Second, P2Y purinoceptor agonists and glycine transporter 1 inhibitors may indirectly inhibit microglia activity by decreasing neuronal or glial glycine release in energy-compromised retina. These inhibitions may have a role in microglia activation, which is present during development and progression of neurodegenerative disorders such as glaucomatous and diabetic retinopathies and age-related macular degeneration or loss of retinal neurons caused by thromboembolic events. We have hypothesized that glycine transporter 1 inhibitors and P2Y purinoceptor agonists may have therapeutic importance in neurodegenerative–neuroinflammatory disorders of the retina by decreasing NR1/NR2B NMDA receptor activity and production and release of a series of proinflammatory cytokines from microglial cells.

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GlyT-1 Inhibitors: From Hits to Clinical Candidates

Cited by 14 publications

References 165 publications

Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity

Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity

The Druggability of Solute Carriers

Purinergic–Glycinergic Interaction in Neurodegenerative and Neuroinflammatory Disorders of the Retina

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