Discovery and hit-to-lead optimization of pyrrolopyrimidines as potent, state-dependent Nav1.7 antagonists

Chakka, Nagasree; Bregman, Howie; Du, Bingfan; Nguyen, Hanh Nho; Buchanan, Joan L.; Feric, Elma; Ligutti, Joseph; Liu, Dong; McDermott, Jeff S.; Zou, Anruo; McDonough, Stefan I.; DiMauro, Erin F.

doi:10.1016/j.bmcl.2012.01.015

Cited by 26 publications

(17 citation statements)

References 15 publications

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“…The first three compounds are known anti-arrhythmic drugs in the market and the last compound is presumably one of the strongest hNa v 1.5 blockers reported so far (IC 50 =20 nm). 80 We depicted the 2D and 3D (top view) ligand interaction diagrams of the four compounds in Figure 12 . As can be seen in the figure, the benzamide aromatic head of ranolazine is flanked between the two aromatic rings of F1760 and W1713, Figure 12A and B .…”

Section: Resultsmentioning

confidence: 99%

Modeling the human Na<sub>v</sub>1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

Ahmed

Hasani

Houghton³

et al. 2017

DDDT

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Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associated with a wide range of cardiac problems and diseases in humans. Current structural models of hNav1.5 are still far from complete and, consequently, their ability to study atomistic interactions of this channel is very limited. Here, we report a comprehensive atomistic model of the hNav1.5 ion channel, constructed using homology modeling technique and refined through long molecular dynamics simulations (680 ns) in the lipid membrane bilayer. Our model was comprehensively validated by using reported mutagenesis data, comparisons with previous models, and binding to a panel of known hNav1.5 blockers. The relatively long classical MD simulation was sufficient to observe a natural sodium permeation event across the channel’s selectivity filters to reach the channel’s central cavity, together with the identification of a unique role of the lysine residue. Electrostatic potential calculations revealed the existence of two potential binding sites for the sodium ion at the outer selectivity filters. To obtain further mechanistic insight into the permeation event from the central cavity to the intracellular region of the channel, we further employed “state-of-the-art” steered molecular dynamics (SMD) simulations. Our SMD simulations revealed two different pathways through which a sodium ion can be expelled from the channel. Further, the SMD simulations identified the key residues that are likely to control these processes. Finally, we discuss the potential binding modes of a panel of known hNav1.5 blockers to our structural model of hNav1.5. We believe that the data presented here will enhance our understanding of the structure–property relationships of the hNav1.5 ion channel and the underlying molecular mechanisms in sodium ion permeation and drug interactions. The results presented here could be useful for designing safer drugs that do not block the hNav1.5 channel.

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Section: Resultsmentioning

confidence: 99%

Modeling the human Na<sub>v</sub>1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

Ahmed

Hasani

Houghton³

et al. 2017

DDDT

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“…Na v channels are involved in a wide array of physiological processes. In particular, Na v 1.7 was clearly identified as playing a crucial role in nociceptive pathways, which led to research into the development of novel therapeutics for pain treatment [6,7,8,9,10,11,12,13,14,15,16,17,18]. For examples, missense mutations of the SCN9A gene that encodes Na v 1.7 produces congenital indifference to pain [19].…”

Section: Introductionmentioning

confidence: 99%

Chemical Synthesis, Proper Folding, Nav Channel Selectivity Profile and Analgesic Properties of the Spider Peptide Phlotoxin 1

Nicolas

Zoukimian

Bosmans

et al. 2019

Toxins

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Phlotoxin-1 (PhlTx1) is a peptide previously identified in tarantula venom (Phlogius species) that belongs to the inhibitory cysteine-knot (ICK) toxin family. Like many ICK-based spider toxins, the synthesis of PhlTx1 appears particularly challenging, mostly for obtaining appropriate folding and concomitant suitable disulfide bridge formation. Herein, we describe a procedure for the chemical synthesis and the directed sequential disulfide bridge formation of PhlTx1 that allows for a straightforward production of this challenging peptide. We also performed extensive functional testing of PhlTx1 on 31 ion channel types and identified the voltage-gated sodium (Nav) channel Nav1.7 as the main target of this toxin. Moreover, we compared PhlTx1 activity to 10 other spider toxin activities on an automated patch-clamp system with Chinese Hamster Ovary (CHO) cells expressing human Nav1.7. Performing these analyses in reproducible conditions allowed for classification according to the potency of the best natural Nav1.7 peptide blockers. Finally, subsequent in vivo testing revealed that intrathecal injection of PhlTx1 reduces the response of mice to formalin in both the acute pain and inflammation phase without signs of neurotoxicity. PhlTx1 is thus an interesting toxin to investigate Nav1.7 involvement in cellular excitability and pain.

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“…Na V 1.7 blockers are currently under development as potential pharmacotherapeutics for pain [30-34]. Hypothalamic dysfunction has not been observed thus far in families with channelopathy-associated insensitivity to pain due to null mutations in the gene encoding Na V 1.7.…”

Section: Discussionmentioning

confidence: 99%

Na_v1.7: Stress-Induced Changes in Immunoreactivity within Magnocellular Neurosecretory Neurons of the Supraoptic Nucleus

et al. 2013

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BackgroundNaV1.7 is preferentially expressed, at relatively high levels, in peripheral neurons, and is often referred to as a “peripheral” sodium channel, and NaV1.7-specific blockers are under study as potential pain therapeutics which might be expected to have minimal CNS side effects. However, occasional reports of patients with NaV1.7 gain-of-function mutations and apparent hypothalamic dysfunction have appeared. The two sodium channels previously studied within the rat hypothalamic supraoptic nucleus, NaV1.2 and NaV1.6, display up-regulated expression in response to osmotic stress.ResultsHere we show that NaV1.7 is present within vasopressin-producing neurons and oxytocin-producing neurons within the rat hypothalamus, and demonstrate that the level of Nav1.7 immunoreactivity is increased in these cells in response to osmotic stress.ConclusionsNaV1.7 is present within neurosecretory neurons of rat supraoptic nucleus, where the level of immunoreactivity is dynamic, increasing in response to osmotic stress. Whether NaV1.7 levels are up-regulated within the human hypothalamus in response to environmental factors or stress, and whether NaV1.7 plays a functional role in human hypothalamus, is not yet known. Until these questions are resolved, the present findings suggest the need for careful assessment of hypothalamic function in patients with NaV1.7 mutations, especially when subjected to stress, and for monitoring of hypothalamic function as NaV1.7 blocking agents are studied.

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Discovery and hit-to-lead optimization of pyrrolopyrimidines as potent, state-dependent Nav1.7 antagonists

Cited by 26 publications

References 15 publications

Modeling the human Na<sub>v</sub>1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

Modeling the human Na<sub>v</sub>1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

Chemical Synthesis, Proper Folding, Nav Channel Selectivity Profile and Analgesic Properties of the Spider Peptide Phlotoxin 1

Na_v1.7: Stress-Induced Changes in Immunoreactivity within Magnocellular Neurosecretory Neurons of the Supraoptic Nucleus

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Discovery and hit-to-lead optimization of pyrrolopyrimidines as potent, state-dependent Nav1.7 antagonists

Cited by 26 publications

References 15 publications

Modeling the human Na<sub>v</sub>1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

Modeling the human Na<sub>v</sub>1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

Chemical Synthesis, Proper Folding, Nav Channel Selectivity Profile and Analgesic Properties of the Spider Peptide Phlotoxin 1

Nav1.7: Stress-Induced Changes in Immunoreactivity within Magnocellular Neurosecretory Neurons of the Supraoptic Nucleus

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Na_v1.7: Stress-Induced Changes in Immunoreactivity within Magnocellular Neurosecretory Neurons of the Supraoptic Nucleus