Inhibition of Na<sub>V</sub>1.7: the possibility of ideal analgesics

Kitano, Yutaka; Shinozuka, Tsuyoshi

doi:10.1039/d2md00081d

Cited by 7 publications

(3 citation statements)

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“…Notwithstanding such reservations, several Na V 1.7-selective drugs have been developed ( Emery et al, 2016 ; Vetter et al, 2017 ; Yang et al, 2018 ) but none have yet passed phase 2 clinical trials ( Kushnarev et al, 2020 ; Alsaloum et al, 2020 ; Eagles et al, 2022 ; Kitano and Shinozuka, 2022 ). This has been attributed to poor target engagement ( Eagles et al, 2022 ; Mulcahy et al, 2019 ; Bankar et al, 2018 ; Kingwell, 2019 ) yet prevention of the flare response by PF-05198007, a Na V 1.7-selective inhibitor, argues that at least some Na V 1.7 channels are blocked ( Alexandrou et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

Xie,

Yang,

Ratté

et al. 2024

eLife

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Nociceptive sensory neurons convey pain signals to the CNS using action potentials. Loss-of-function mutations in the voltage-gated sodium channel NaV1.7 cause insensitivity to pain (presumably by reducing nociceptor excitability) but efforts to treat pain by inhibiting NaV1.7 pharmacologically have largely failed. This may reflect the variable contribution of NaV1.7 to nociceptor excitability. Contrary to claims that NaV1.7 is necessary for nociceptors to initiate action potentials, we show that nociceptors can achieve equivalent excitability using different combinations of NaV1.3, NaV1.7, and NaV1.8. Selectively blocking one of those NaV subtypes reduces nociceptor excitability only if the other two subtypes are weakly expressed. For example, excitability relies on NaV1.8 in acutely dissociated nociceptors but responsibility shifts to NaV1.7 and NaV1.3 by the fourth day in culture. A similar shift in NaV dependence occurs in vivo after inflammation, impacting ability of the NaV1.7-selective inhibitor PF-05089771 to reduce pain in behavioral tests. Flexible use of different NaV subtypes â€“ an example of degeneracy â€“ compromises the reliable modulation of nociceptor excitability by subtype-selective inhibitors. Identifying the dominant NaV subtype to predict drug efficacy is not trivial. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level. Nociceptors can achieve equivalent excitability using different sodium channel subtypes. The analgesic efficacy of subtype-selective drugs hinges on which subtype controls excitability. This contingency likely contributes to poor clinical outcomes.

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Section: Introductionmentioning

confidence: 99%

Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

Xie,

Yang,

Ratté

et al. 2024

eLife

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“…Notwithstanding such reservations, several Na V 1.7-selective drugs have been developed (30)(31)(32) but none have yet passed phase 2 clinical trials (33)(34)(35)(36). This has been attributed to poor target engagement (35,(37)(38)(39) yet prevention of the flare response by PF-05198007, a Na V 1.7-selective inhibitor, argues that at least some Na V 1.7 channels are blocked (40).…”

Section: Introductionmentioning

confidence: 99%

Equivalent excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

Xie

Yang

Ratté

et al. 2022

Preprint

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Nociceptive sensory neurons convey pain signals to the CNS. Nociceptor hyperexcitability amplifies those signals, causing pain hypersensitivity. Reducing nociceptor excitability should mitigate that hypersensitivity, consistent with the effects of loss-of-function mutations in voltage-gated sodium (NaV) channels like NaV1.7. Yet efforts to phenocopy such mutations pharmacologically have failed in clinical trials. This failure may stem from the degenerate nature of nociceptor excitability. Here, we show that nociceptors can achieve equivalent excitability using different combinations of NaV1.3, NaV1.7, and NaV1.8. If NaV1.3 and/or NaV1.8 levels are high enough to maintain nociceptor excitability, selectively blocking NaV1.7 (e.g. with PF-05089771) becomes inconsequential. We demonstrate shifts in drug efficacy by comparing neurons tested after different numbers of days in vitro (DIV): Nociceptor excitability relies on NaV1.8 at DIV0 but that responsibility shifts to NaV1.7 and NaV1.3 on DIV4-7. A similar shift in NaV-dependence occurs in vivo, following inflammation, and impacts the ability of PF-05089771 to modulate pain sensitivity. These results demonstrate that nociceptors are surprisingly flexible in using different NaV isoforms to regulate excitability. This flexibility poses a serious problem for subtype-selective drugs whose efficacy hinges on such vagaries. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level.

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“…Although PF-05089771 was well tolerated, the elevation of cholesterol levels was reported in phase 2 clinical trial . Thus, further R&D activities are essential for acquiring novel analgesic agents. − …”

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confidence: 99%

N-Aryl Indoles as a Novel Class of Potent Na_V1.7 Inhibitors

Karanjule

Hayashi

Suzuki

et al. 2023

ACS Med. Chem. Lett.

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A novel class of potent NaV1.7 inhibitors has been discovered. The replacement of diaryl ether in compound I was investigated to enhance mouse NaV1.7 inhibitory activity, which resulted in the discovery of N-aryl indoles. The introduction of the 3-methyl group is crucial for high NaV1.7 in vitro potency. The adjustment of lipophilicity led to the discovery of 2e. Compound 2e (DS43260857) demonstrated high in vitro potencies against both human and mouse NaV1.7 with high selectivity over NaV1.1, NaV1.5, and hERG. In vivo evaluations revealed 2e demonstrating potent efficacy in PSL mice with excellent pharmacokinetics.

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Inhibition of Na_V1.7: the possibility of ideal analgesics

Abstract: The selective inhibition of NaV1.7 is a promising strategy for developing novel analgesic agents with fewer adverse effects. Although the potent selective inhibition of NaV1.7 has been recently achieved, multiple...

Cited by 7 publications

References 159 publications

Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

Equivalent excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

N-Aryl Indoles as a Novel Class of Potent Na_V1.7 Inhibitors

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Inhibition of NaV1.7: the possibility of ideal analgesics

Abstract: The selective inhibition of NaV1.7 is a promising strategy for developing novel analgesic agents with fewer adverse effects. Although the potent selective inhibition of NaV1.7 has been recently achieved, multiple...

Cited by 7 publications

References 159 publications

Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

Equivalent excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

N-Aryl Indoles as a Novel Class of Potent NaV1.7 Inhibitors

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Inhibition of Na_V1.7: the possibility of ideal analgesics

N-Aryl Indoles as a Novel Class of Potent Na_V1.7 Inhibitors