Abstract
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 2RS,4RS-39c (pIC50 (mGAT4) = 5.36), 50a (pIC50 (mGAT2) = 5.43), and 56a (with moderate subtype selectivity that favored mGAT4, pIC50 (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.
Highlights
The γ-aminobutyric acid (GABA) is a neurotransmitter known for its inhibitory modulation of neuronal networks.1,2 Endogenous GABA is synthesized from glutamate3,4 and controls the generation of membrane potential oscillations by acting on two types of receptors, ionotropic (GABAA) and metabotropic (GABAB) as summarized in Figure 1.5 Plasma membrane transporters of GABA (GATs) are components of one of the pathways responsible for terminating inhibitory signaling
The results presented as a percent represent [3H]GABA uptake or NO711 binding in the presence of 100 μM inhibitor
It is worth pointing out that painful diabetic neuropathy is a major complication of diabetes and a cause of increased mortality
Summary
The γ-aminobutyric acid (GABA) is a neurotransmitter known for its inhibitory modulation of neuronal networks. Endogenous GABA is synthesized from glutamate and controls the generation of membrane potential oscillations by acting on two types of receptors, ionotropic (GABAA) and metabotropic (GABAB) as summarized in Figure 1.5 Plasma membrane transporters of GABA (GATs) are components of one of the pathways responsible for terminating inhibitory signaling. Endogenous GABA is synthesized from glutamate and controls the generation of membrane potential oscillations by acting on two types of receptors, ionotropic (GABAA) and metabotropic (GABAB) as summarized in Figure 1.5 Plasma membrane transporters of GABA (GATs) are components of one of the pathways responsible for terminating inhibitory signaling. GATs expression in different cell types is highly dynamic and can be modified depending on the activity. Reuptake achieved through GATs occurs in nerve terminals (allowing GABA to be recycled as a neurotransmitter) and/or the surrounding glial cells, whereby glial GATs are responsible for 20% reuptake of GABA, Figure 1.6. GABA specific transport systems represent a mechanism that regulates the efficiency of GABA transmission; since 1990, the family of GAT sodium symporters has become an interesting biological target. GATs have a confusing numbering system; we present a summary of the current nomenclature based on that from the International
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