Novel mouse GABA uptake inhibitors with enhanced inhibitory activity toward mGAT3/4 and their effect on pain threshold in mice

Zaręba, Paula; Gryzło, Beata; Malawska, Katarzyna; Sałat, Kinga; Höfner, Georg; Nowaczyk, Alicja; Fijałkowski, Łukasz; Rapacz, Anna; Podkowa, Adrian; Furgała, Agata; Żmudzki, Paweł; Wanner, Klaus T.; Malawska, Barbara; Kulig, Katarzyna

doi:10.1016/j.ejmech.2019.111920

Cited by 12 publications

(13 citation statements)

References 72 publications

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“…Restoration of GABA levels specifically in the brain or non-specifically in the spinal cord and brain can reduce CIPN symptoms, and multiple analgesic drugs for CIPN control balance of inhibitory and excitatory transmission. Clinically, GABA and GABA analogs have been investigated as potential analgesics in CIPN and other conditions (Zaręba et al, 2020) because GABAergic neurons and receptors are involved in coordination of the perception and response to noxious stimuli (Enna and McCarson, 2006). However, GABAergic drugs are not commonly used as analgesics given their side effects such as muscle weakness, drowsiness, fatigue, upset stomach, and nausea (Enna and McCarson, 2006).…”

Section: Decreased Gabaergic Inhibitionmentioning

confidence: 99%

Review of the Role of the Brain in Chemotherapy-Induced Peripheral Neuropathy

Omran

Belcher

Mohile

et al. 2021

Front. Mol. Biosci.

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Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating, and dose-limiting side effect of many chemotherapy regimens yet has limited treatments due to incomplete knowledge of its pathophysiology. Research on the pathophysiology of CIPN has focused on peripheral nerves because CIPN symptoms are felt in the hands and feet. However, better understanding the role of the brain in CIPN may accelerate understanding, diagnosing, and treating CIPN. The goals of this review are to (1) investigate the role of the brain in CIPN, and (2) use this knowledge to inform future research and treatment of CIPN. We identified 16 papers using brain interventions in animal models of CIPN and five papers using brain imaging in humans or monkeys with CIPN. These studies suggest that CIPN is partly caused by (1) brain hyperactivity, (2) reduced GABAergic inhibition, (3) neuroinflammation, and (4) overactivation of GPCR/MAPK pathways. These four features were observed in several brain regions including the thalamus, periaqueductal gray, anterior cingulate cortex, somatosensory cortex, and insula. We discuss how to leverage this knowledge for future preclinical research, clinical research, and brain-based treatments for CIPN.

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Section: Decreased Gabaergic Inhibitionmentioning

confidence: 99%

Review of the Role of the Brain in Chemotherapy-Induced Peripheral Neuropathy

Omran

Belcher

Mohile

et al. 2021

Front. Mol. Biosci.

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“… 41 Then, aminolysis was conducted following previously described synthetic procedures. 25 , 41 − 44 Compounds 37a – c , 39a – c , 41 , 43a , b , and 45 were isolated in pure form as a mixture of racemic diastereomers, e.g., 2 RS ,4 RS - 45 and 2 RS ,4 SR - 45 , with a diastereoselectivity (ds) of approximately 7:3 (see the experimental section).…”

Section: Resultsmentioning

confidence: 99%

“…Acetylation of 50a and 50b gave 51a and 51b, respectively (Scheme 2). 25,46 2.1.2. Synthesis of 3-Hydroxypropanamide Derivatives (54a−c, 55a−e, 56a−e, 57, 58, and 59a−c).…”

Section: Resultsmentioning

confidence: 99%

“…We previously obtained a series of GABA analogs with mGAT3/4 subtype preference with the most interesting compound 13 that could reduce tactile allodynia in neuropathic mice. 25 In this paper, we present a continuation of our previous work with new derivatives that can be classified as analogs of parent compound 13 . A summary of these modifications is presented in Figure 3 .…”

Section: Introductionmentioning

confidence: 99%

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Novel Functionalized Amino Acids as Inhibitors of GABA Transporters with Analgesic Activity

Gryzło

Zaręba

Malawska

et al. 2021

ACS Chem. Neurosci.

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Neuropathic pain resistance to pharmacotherapy has encouraged researchers to develop effective therapies for its treatment. γ-Aminobutyric acid (GABA) transporters 1 and 4 (mGAT1 and mGAT4) have been increasingly recognized as promising drug targets for neuropathic pain (NP) associated with imbalances in inhibitory neurotransmission. In this context, we designed and synthesized new functionalized amino acids as inhibitors of GABA uptake and assessed their activities toward all four mouse GAT subtypes (mGAT1–4). According to the obtained results, compounds 2 RS ,4 RS - 39c (pIC 50 (mGAT4) = 5.36), 50a (pIC 50 (mGAT2) = 5.43), and 56a (with moderate subtype selectivity that favored mGAT4, pIC 50 (mGAT4) = 5.04) were of particular interest and were therefore evaluated for their cytotoxic and hepatotoxic effects. In a set of in vivo experiments, both compounds 50a and 56a showed antinociceptive properties in three rodent models of NP, namely, chemotherapy-induced neuropathic pain models (the oxaliplatin model and the paclitaxel model) and the diabetic neuropathic pain model induced by streptozotocin; however compound 56a demonstrated predominant activity. Since impaired motor coordination is also observed in neuropathic pain conditions, we have pointed out that none of the test compounds induced motor deficits in the rotarod test.

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“…The effect of non-GAT-1 inhibitors on the behavioral symptoms of CIPN is less known; however recent studies have shown that preferential inhibitors of mouse GAT3/4 might attenuate tactile allodynia but not cold allodynia in oxaliplatin-treated mice [178].…”

Section: Central Nervous System Structures and Neurotransmittersmentioning

confidence: 99%

Chemotherapy-induced peripheral neuropathy: part 1—current state of knowledge and perspectives for pharmacotherapy

Sałat

2020

Pharmacol. Rep

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Background Despite the increasing knowledge of the etiology of neuropathic pain, this type of chronic pain is resistant to available analgesics in approximately 50% of patients and therefore is continuously a subject of considerable interest for physiologists, neurologists, medicinal chemists, pharmacologists and others searching for more effective treatment options for this debilitating condition. Materials and methods The present review article is the first of the two articles focused on chemotherapy-induced peripheral neuropathy (CIPN). Results CIPN is regarded as one of the most common drug-induced neuropathies and is highly pharmacoresistant. The lack of efficacious pharmacological methods for treating CIPN and preventing its development makes CIPN-related neuropathic pain a serious therapeutic gap in current medicine and pharmacotherapy. In this paper, the most recent advances in the field of studies on CIPN caused by platinum compounds (namely oxaliplatin and cisplatin), taxanes, vinca alkaloids and bortezomib are summarized. Conclusions The prevalence of CIPN, potential causes, risk factors, symptoms and molecular mechanisms underlying this pharmacoresistant condition are discussed.

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Novel mouse GABA uptake inhibitors with enhanced inhibitory activity toward mGAT3/4 and their effect on pain threshold in mice

Cited by 12 publications

References 72 publications

Review of the Role of the Brain in Chemotherapy-Induced Peripheral Neuropathy

Review of the Role of the Brain in Chemotherapy-Induced Peripheral Neuropathy

Novel Functionalized Amino Acids as Inhibitors of GABA Transporters with Analgesic Activity

Chemotherapy-induced peripheral neuropathy: part 1—current state of knowledge and perspectives for pharmacotherapy

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