Design, synthesis and biological evaluation of small-azo-dyes as potent Vesicular Glutamate Transporters inhibitors

Favre-Besse, Franck-Cyril; Poirel, Odile; Bersot, Tiphaine; Kim-Grellier, Elodie; Daumas, Stéphanie; Mestikawy, Salah El; Acher, Francine; Pietrancosta, Nicolas

doi:10.1016/j.ejmech.2014.03.056

Cited by 25 publications

(13 citation statements)

References 31 publications

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“…To efficiently interact with VGLUTs, compounds should bear two hydrophilic motifs separated by a hydrophobic linker (Kehrl et al, 2017). Previous work has shown that a shorter molecule bearing only one hydrophobic and one hydrophilic counterpart led to drastic loss of inhibitory activity (Carrigan et al, 2002;Favre-Besse et al, 2014 Chicago Sky Blue (EC50 = 0.3-3µM, not shown) confirmed the potentiality of modifying the hydrophobic linker (Fig. 1b).…”

Section: Methodsmentioning

confidence: 52%

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LSP5-2157 a new inhibitor of vesicular glutamate transporters

et al. 2020

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Vesicular glutamate transporters (VGLUT1-3) mediate the uptake of glutamate into synaptic vesicles. VGLUTs are pivotal actors of excitatory transmission and therefore of all brain functions. Their implication in various pathologies such as Parkinson and Alzheimer disease, epilepsy, schizophrenia, anxiety, addiction or deafness has been clearly documented. Despite their functional importance, the pharmacology of VGLUTs is particularly underdeveloped and limited at non-specific dyes such as Trypan Blue, Rose Bengal or Brillant Yellow type. Here we report the design and the conception of new potent analogs based on Trypan Blue scaffold. Our best compound, named LSP5-2157, has an EC50 of 50nM on glutamate vesicular uptake. Using a 3D homology model, we determined putative binding subdomains of VGLUT1 that bind LSP5-2157. To better estimate the specificity and potency of LSP5-2157, we investigated its ability to block glutamatergic transmission in autaptic hippocampal cells. Neither ionotropic glutamate receptors nor GABAergic transmission or transmission machinery such as Ca 2+ channels were affected by application of LSP5-2157. Low doses of LSP5-2157 (2µM) reversibly reduce glutamatergic neurotransmission in hippocampal autpases. LSP5-2157 had a low and depressing effect on synaptic efficacy in hippocampal slice. Furthermore, LSP5-2157 (2µM) had no effect on NMDA-R-mediated fEPSP. This compound was able to reduce synaptic plasticity induced by 3 trains of 100Hz. However, LSP5-2157 had no effect on plasticity induced by theta burst, which suggests that the readily releasable pool of glutamate was not affected by the drug. Finally, we showed that LSP5-2157 had the capacity to inhibit VGLUT3-dependent auditory synaptic transmission in the guinea pig cochlea. In this model, LSP5-2157 abolished the compound action potential of auditory nerve at high concentration showing the limitation of LSP5-2157 permeation in an in-vivo model. Therefore, the new ligand LSP5-2157 has a high affinity for VGLUTs and shows some permeability in isolated neuron, tissue preparations or in vivo in the auditory system. These findings open the way to the use of VGLUTs inhibitors to assess glutamatergic functions in vitro and in vivo.

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Section: Methodsmentioning

confidence: 52%

“…Compounds were synthesized according to procedure already described (Favre-Besse et al, 2014) with minor modifications. (Supplementary Methods) Glutamate vesicular uptake Vesicular Glutamate uptake was assayed as previously described (Kish and Ueda, 1989;Naito and Ueda, 1985;Pietrancosta et al, 2010) with minor modifications.…”

Section: Synthesismentioning

confidence: 99%

LSP5-2157 a new inhibitor of vesicular glutamate transporters

et al. 2020

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“…This distance is similar in Brilliant Yellow (d (NO-) = 9.324 Å), trypan blue (d (NO-) = 9.799 Å) and Violet Direct 51 (d (NO-) = 8.274 Å, from (NO) = 10.354 Å) [296]. The negative charges of the naphthyl-disulphonic polar motif also play an important role in the inhibition of VGLUTs [297] (Scheme 7).…”

Section: Azoic Dyesmentioning

confidence: 70%

“…This NH 2 does not seem to be essential for glutamate affinity [296]. Currently, azo dyes that inhibit VGLUTs with the best affinity are as follows: Bright Yellow (BY, IC 50 SAR studies have identified important pharmacophoric sites for the affinity of azo dyes (e.g., TB) [296,297]. These studies highlighted the importance of the hydrophobic aryl motif.…”

Section: Azoic Dyesmentioning

confidence: 99%

Molecular, Structural, Functional, and Pharmacological Sites for Vesicular Glutamate Transporter Regulation

et al. 2020

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Vesicular glutamate transporters (VGLUTs) control quantal size of glutamatergic transmission and have been the center of numerous studies over the past two decades. VGLUTs contain two independent transport modes that facilitate glutamate packaging into synaptic vesicles and phosphate (Pi) ion transport into the synaptic terminal. While a transmembrane proton electrical gradient established by a vacuolar-type ATPase powers vesicular glutamate transport, recent studies indicate that binding sites and flux properties for chloride, potassium, and protons within VGLUTs themselves regulate VGLUT activity as well. These intrinsic ionic binding and flux properties of VGLUTs can therefore be modulated by neurophysiological conditions to affect levels of glutamate available for release from synapses. Despite their extraordinary importance, specific and high-affinity pharmacological compounds that interact with these sites and regulate VGLUT function, distinguish between the various modes of transport, and the different isoforms themselves, are lacking. In this review, we provide an overview of the physiologic sites for VGLUT regulation that could modulate glutamate release in an over-active synapse or in a disease state.

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“…Azo dyes are one of the most significant classes of chromophores with diverse applications in science and industry, with simplistic synthesis approach can yield a broad spectrum derivatives. Specifically, the synthesis of heterocyclic azo dyes has gained particular attention from the several decades as they exhibit antifungal, anti-convulsant, anti-inflammatory, anti-tubercular, DNA binding and analgesic properties [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Pyridine Scaffolds, Phenols and Derivatives of Azo Moiety: Current Therapeutic Perspectives

et al. 2021

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Synthetic heterocyclic compounds have incredible potential against different diseases; pyridines, phenolic compounds and the derivatives of azo moiety have shown excellent antimicrobial, antiviral, antidiabetic, anti-melanogenic, anti-ulcer, anticancer, anti-mycobacterial, anti-inflammatory, DNA binding and chemosensing activities. In the present review, the above-mentioned activities of the nitrogen-containing heterocyclic compounds (pyridines), hydroxyl (phenols) and azo derivatives are discussed with reference to the minimum inhibitory concentration and structure–activity relationship, which clearly indicate that the presence of nitrogen in the phenyl ring; in addition, the hydroxyl substituent and the incorporation of a diazo group is crucial for the improved efficacies of the compounds in probing different diseases. The comparison was made with the reported drugs and new synthetic derivatives that showed recent therapeutic perspectives made in the last five years.

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Design, synthesis and biological evaluation of small-azo-dyes as potent Vesicular Glutamate Transporters inhibitors

Cited by 25 publications

References 31 publications

LSP5-2157 a new inhibitor of vesicular glutamate transporters

LSP5-2157 a new inhibitor of vesicular glutamate transporters

Molecular, Structural, Functional, and Pharmacological Sites for Vesicular Glutamate Transporter Regulation

Pyridine Scaffolds, Phenols and Derivatives of Azo Moiety: Current Therapeutic Perspectives

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