The Antinociceptive Effect of SNAP5114, a Gamma-Aminobutyric Acid Transporter-3 Inhibitor, in Rat Experimental Pain Models

Kataoka, Kazunori; Hara, Koji; Haranishi, Yasunori; Terada, Tadanori; Sata, Takeyoshi

doi:10.1213/ane.0b013e318282dda7

Cited by 28 publications

(22 citation statements)

References 34 publications

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“…Additionally, GAT1 knockout mice exhibit lower basal levels of anxiety-like and depressive-like behaviors as well as a lower basal plasma CORT (Liu et al, 2007), findings that were replicated with chronic dosing of the GAT1 inhibitor tiagabine (Thoeringer et al, 2010). Recent studies testing a GAT3 inhibitor, SNAP5114 (1-[2-[tris (4-methoxyphenyl)methoxy]ethyl]-(S)-3-piperidinecarboxylic acid), found antinociception in response to mechanical and thermal stimuli via an interaction with both GABA A and GABA B receptors (Kataoka et al, 2013). However, SNAP5114 did not change withdrawal thresholds in a mouse SNL model, whereas NNC05-2090 (1-[3-(9H-carbazol-9-yl)propyl]-4-(2-methoxyphenyl)-4-piperidinol hydrochloride), a betaine/GAT1 inhibitor, demonstrated efficacy (Jinzenji et al, 2014).…”

Section: Novel Targets For Stress-induced Painmentioning

confidence: 92%

Stress-Induced Pain: A Target for the Development of Novel Therapeutics

Johnson

Meerveld

2014

J Pharmacol Exp Ther

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Although current therapeutics provide relief from acute pain, drugs used for treatment of chronic pain are typically less efficacious and limited by adverse side effects, including tolerance, addiction, and gastrointestinal upset. Thus, there is a significant need for novel therapies for the treatment of chronic pain. In concert with chronic pain, persistent stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic pain disorders. Stress exacerbation of chronic pain suggests that centrally acting drugs targeting the pain-and stress-responsive brain regions represent a valid target for the development of novel therapeutics. This review provides an overview of how stress modulates spinal and central pain pathways, identifies key neurotransmitters and receptors within these pathways, and highlights their potential as novel targets for therapeutics to treat chronic pain.

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Section: Novel Targets For Stress-induced Painmentioning

confidence: 92%

Stress-Induced Pain: A Target for the Development of Novel Therapeutics

Johnson

Meerveld

2014

J Pharmacol Exp Ther

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“…A study by Kataoka et al [66] investigated the role of GAT-3 by administering differing doses of a GAT-3 inhibitor to different, rodent-based pain models. Specifically, Kataoka et al [66] applied thermal, mechanical, and chemical stimuli to induce pain in the subjects, followed by administration of a GAT-3 inhibitor.…”

Section: How Do Pharmacological Interventions Take Advantage Of Pamentioning

confidence: 99%

Section: How Do Pharmacological Interventions Take Advantage Of Pamentioning

confidence: 99%

“…Specifically, Kataoka et al [66] applied thermal, mechanical, and chemical stimuli to induce pain in the subjects, followed by administration of a GAT-3 inhibitor. The result was an increase in the withdrawal threshold (indicative of pain) in the thermal pain model without an observed change in the rat's response to mechanical pain [66]. Interestingly, while GAT-3 inhibition did not affect chemically-induced pain in the early model, it was observed to inhibit the nociceptive response to persistent chemically-induced pain [66].…”

Section: How Do Pharmacological Interventions Take Advantage Of Pamentioning

confidence: 99%

“…The result was an increase in the withdrawal threshold (indicative of pain) in the thermal pain model without an observed change in the rat's response to mechanical pain [66]. Interestingly, while GAT-3 inhibition did not affect chemically-induced pain in the early model, it was observed to inhibit the nociceptive response to persistent chemically-induced pain [66]. Katoaka et al [66] concluded that GAT-3 inhibitors could have utility in treating pain in clinical practice, especially in the setting of acute thermal injury and chronic neuropathic pain.…”

Section: How Do Pharmacological Interventions Take Advantage Of Pamentioning

confidence: 99%

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Transmission pathways and mediators as the basis for clinical pharmacology of pain

Kirkpatrick

McEntire

Smith

et al. 2016

Expert Review of Clinical Pharmacology

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Introduction Mediators in pain transmission are the targets of a multitude of different analgesic pharmaceuticals. This review explores the most significant mediators of pain transmission as well as the pharmaceuticals that act on them. Areas Covered The review explores many of the key mediators of pain transmission. In doing so, this review uncovers important areas for further research. It also highlights agents with potential for producing novel analgesics, probes important interactions between pain transmission pathways that could contribute to synergistic analgesia, and emphasizes transmission factors that participate in transforming acute injury into chronic pain. Expert Commentary This review examines current pain research, particularly in the context of identifying novel analgesics, highlighting interactions between analgesic transmission pathways, and discussing factors that may contribute to the development of chronic pain after an acute injury.

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Multifunctional, Fluorene‐Based Modulator of Cholinergic and GABAergic Neurotransmission as a Novel Drug Candidate for Palliative Treatment of Alzheimer's Disease

Panek,

Pasieka,

Jończyk

et al. 2024

Angewandte Chemie

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and behavioral and psychological symptoms of dementia (BPSD). Given that cholinergic neurons are predominantly affected in AD, current treatments primarily aim to enhance cholinergic neurotransmission. However, imbalances in other neurotransmitters, such as γ‐aminobutyric acid (GABA), also contribute to AD symptomatology. In the presented research, by using a combination of crystallography and computational methods we developed 6 as a dual modulator of GABAergic and cholinergic neurotransmission systems. Compound 6 demonstrated inhibition of BuChE (IC50 = 0.21 μM) and GABA transporter 1 (IC50 = 10.96 μM) and 3 (IC50 = 7.76 μM), along with a favorable drug‐likeness profile. Subsequent in vivo studies revealed effectiveness of 6 in enhancing memory retention and alleviating anxiety and depression symptoms in animal models, while also proving safe and bioavailable for oral administration. The innovative multi‐target‐directed ligand 6 offers a new approach to treating cognitive deficits and BPSD in AD.

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The Antinociceptive Effect of SNAP5114, a Gamma-Aminobutyric Acid Transporter-3 Inhibitor, in Rat Experimental Pain Models

Abstract: These results suggest that SNAP5114 exerts antinociceptive effects by activating GABAA and GABAB receptors in the spinal cord. The GAT-3 inhibitor may prove useful in treatment of various painful conditions.

Cited by 28 publications

References 34 publications

Stress-Induced Pain: A Target for the Development of Novel Therapeutics

Stress-Induced Pain: A Target for the Development of Novel Therapeutics

Transmission pathways and mediators as the basis for clinical pharmacology of pain

Multifunctional, Fluorene‐Based Modulator of Cholinergic and GABAergic Neurotransmission as a Novel Drug Candidate for Palliative Treatment of Alzheimer's Disease

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