Correcting a widespread error: Neuroprotectant N-acetyl-L-tryptophan does not bind to the neurokinin-1 receptor

Matalińska, Joanna; Lipiński, Piotr F. J.

doi:10.1016/j.mcn.2022.103728

Cited by 6 publications

(5 citation statements)

References 91 publications

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“…The binding plot and the statistics were calculated using GraphPad Prism [63] . The hNK1R binding data for Substance P, aprepitant, L732,138 and compound 6 were measured in our laboratory following the same protocol and were already reported in our previous papers [17,64] …”

Section: Methodsmentioning

confidence: 99%

Moving out of CF₃‐Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF₅) Group

Witoszka,

Matalińska,

Misicka

et al. 2023

ChemMedChem

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The NK1 receptor (NK1R) is a molecular target for both approved and experimental drugs intended for a variety of conditions, including i.a. emesis, pain or cancers. While contemplating modifications to the typical NK1R pharmacophore, we wondered whether the CF3 groups common for many NK1R ligands, could be replaced with some other moiety. Our attention was drawn by the SF5‐group, and so we designed, synthesized and tested for NK1R affinity ten novel SF5‐containing compounds. All the novel analogues exhibit detectable NK1R binding, with the best of them, compound 5a, binding only slightly worse (IC50 = 34.3 nM) than the approved NK1R‐targeting drug, aprepitant (IC50 = 27.7 nM). Molecular docking provided structural explanation of SAR. According to our analysis, the SF5 group in our compounds occupies a position similar to that of one of CF3 groups of aprepitant as found in the crystal structure. Additionally, we checked on whether the docking scoring function or energies derived from Fragment Molecular Orbital quantum chemical calculations may be helpful in explaining and predicting the experimental receptor affinities for our analogues. Both these methods produce moderately good results. Overall, this is the first demonstration of the utility of the SF5‐group in the design of NK1R ligands.

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Section: Methodsmentioning

confidence: 99%

Moving out of CF₃‐Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF₅) Group

Witoszka,

Matalińska,

Misicka

et al. 2023

ChemMedChem

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“…It is also worth noting that a substantial number of in vivo studies examining the role of SP and the NK1R have used N-acetyl-L-tryptophan (NAT) as an agent with assumed NK1R antagonist activity, primarily based on the reported activities of analogues of L-tryptophan [110]. Specific NK1R binding of NAT has not been characterised, and a recent publication has demonstrated a lack of NK1R binding by NAT [111]. However, an in silico screening assay for NK1R antagonist activity predicted that NAT would have favourable binding characteristics [112].…”

Section: Non-neuronal Nk1 Receptor Activity In the Cnsmentioning

confidence: 99%

“…However, an in silico screening assay for NK1R antagonist activity predicted that NAT would have favourable binding characteristics [112]. In line with the concerns raised by Matalinska and Lipinski [111], it is appropriate that further studies investigating the role of NK1R in neuropathologies should utilise selective NK1R antagonists. That said, there have also been in vivo studies where positive neuroprotective outcomes assigned to the supposed NK1-mediated action of NAT have subsequently been fully replicated with highly selective NK1 antagonists [113][114][115][116][117].…”

Section: Non-neuronal Nk1 Receptor Activity In the Cnsmentioning

confidence: 99%

Evidence for the Involvement of the Tachykinin NK1 Receptor in Acute Inflammation of the Central Nervous System

Turner,

Nimmo

2023

Receptors

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Neuroinflammation is considered to be a significant component in a range of neuropathologies. Unfortunately, whilst its role is well recognised, the options for therapeutic intervention are limited. As such, there is a need to identify novel targets in order to increase treatment options. Given its role as both a neurotransmitter and an immune modulator, substance P (SP) and its NK1 receptor (NK1R) have been widely studied as a potential therapeutic target. There is evidence that NK1R antagonists may exert beneficial effects in a range of conditions, including traumatic brain injury and stroke. Blocking the NK1R has been shown to reduce blood–brain barrier dysfunction, reduce cerebral oedema, and reduce the levels of pro-inflammatory cytokines. These actions are associated with improved survival and functional outcomes. The NK1R has also been shown to be involved in the inflammatory reaction to CNS infection, and hence antagonists may have some benefit in reducing infection-driven inflammation. However, the NK1R may also play a role in the host immune response to infection, and so here, the potential beneficial and detrimental effects need to be carefully balanced. The purpose of this review is to provide a summary of evidence for the involvement of the NK1R in acute CNS inflammation, particularly in the context of traumatic brain injury and stroke.

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“…The move away from NAT in experimental studies was useful not only to address its inability to cross the intact BBB but also because of controversies surrounding its classification as an NK1 antagonist. While some studies have definitively shown that NAT binds to and inhibits the NK1 receptor as well as presynaptic substance P release [37], others have been unable to confirm NK1 receptor binding [38]. In circumventing these issues, studies using alternative BBB permeable NK1 antagonists may better facilitate clinical translation, particularly EUC-001, which is a highly selective antagonist of the human NK1 receptor, is a water-soluble yet membrane-permeable compound, and has few potential drug-drug interactions [19].…”

Section: Moderate Tbimentioning

confidence: 99%

The Role of Substance P and NK1 Receptors in Mild to Severe Traumatic Brain Injury: From CTE to ICP

Vink,

Corrigan

2023

Receptors

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Binding of substance P to the tachykinin NK1 receptor is involved in numerous physiological and pathophysiological processes ranging from modulation of sensory and motor function to inflammation, cancer, and brain injury, amongst others. NK1 antagonists therefore have enormous potential as a therapeutic intervention in a wide variety of human disease states, albeit that the clinical potential is yet to be fully realised. In the current review, the role of substance P in the pathophysiology of traumatic brain injury (TBI) will be discussed, summarising both experimental and clinical observations in mild, moderate, and severe TBI. In addition, the potential for NK1 antagonists to be a valuable therapeutic intervention against chronic traumatic encephalopathy (CTE) after repeated concussive brain injury as well as raised intracranial pressure (ICP) following severe TBI will be addressed, highlighting the various pathophysiological processes that are attenuated by the intervention.

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Correcting a widespread error: Neuroprotectant N-acetyl-L-tryptophan does not bind to the neurokinin-1 receptor

Cited by 6 publications

References 91 publications

Moving out of CF₃‐Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF₅) Group

Moving out of CF₃‐Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF₅) Group

Evidence for the Involvement of the Tachykinin NK1 Receptor in Acute Inflammation of the Central Nervous System

The Role of Substance P and NK1 Receptors in Mild to Severe Traumatic Brain Injury: From CTE to ICP

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Correcting a widespread error: Neuroprotectant N-acetyl-L-tryptophan does not bind to the neurokinin-1 receptor

Cited by 6 publications

References 91 publications

Moving out of CF3‐Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF5) Group

Moving out of CF3‐Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF5) Group

Evidence for the Involvement of the Tachykinin NK1 Receptor in Acute Inflammation of the Central Nervous System

The Role of Substance P and NK1 Receptors in Mild to Severe Traumatic Brain Injury: From CTE to ICP

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Product

Resources

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Moving out of CF₃‐Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF₅) Group

Moving out of CF₃‐Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF₅) Group