Inhibition of N-type calcium channels by phenoxyanilide analogues

Anjie S. Bispat; Fernanda C. Cardoso; Mahadhi Hasan; Callum E. Adams; Richard J. Lewis; Peter J. Duggan; Kellie L. Tuck

doi:10.1016/j.bmc.2025.118449

Inhibition of N-type calcium channels by phenoxyanilide analogues

Anjie S. Bispat
, Fernanda C. Cardoso
, Mahadhi Hasan
, Callum E. Adams
, Richard J. Lewis
, Peter J. Duggan
, Kellie L. Tuck

College of Science and Engineering

Research output: Contribution to journal › Article › peer-review

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Abstract

A series of N,N-dimethylated phenoxyanilide analogues were synthesised and evaluated for their activity at Ca_V2.2 and Ca_V3.2 channels. The SAR study conducted, highlighted that steric and hydrophobic interactions primarily enhanced the affinity for the Ca_V2.2 channel, while an electron-rich aromatic phenoxy ring (R) favoured Ca_V3.2 inhibition. Whilst the -CF₃phenoxyanilide compounds exhibited a high potency for the Ca_V2.2 channel, their low CNS MPO scores and high lipophilicity were indicative of a reduced likelihood of crossing the blood-brain barrier (BBB) and suboptimal physicochemical characteristics. The outcomes of this investigation provided valuable insights into the development of selective calcium channel inhibitors for the treatment of neuropathic pain, while building on previous SAR studies performed within the research group.

Original language	English
Article number	118449
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	132
DOIs	https://doi.org/10.1016/j.bmc.2025.118449
Publication status	Published - 1 Jan 2026

Keywords

Ca2.2
Ca3.2
N-type calcium channel
Pain
Phenoxyanilide
T-type calcium channel

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10.1016/j.bmc.2025.118449Licence: CC BY-NC-ND

Final published versionFinal published version, 2.04 MBLicence: CC BY-NC-ND

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title = "Inhibition of N-type calcium channels by phenoxyanilide analogues",

abstract = "A series of N,N-dimethylated phenoxyanilide analogues were synthesised and evaluated for their activity at CaV2.2 and CaV3.2 channels. The SAR study conducted, highlighted that steric and hydrophobic interactions primarily enhanced the affinity for the CaV2.2 channel, while an electron-rich aromatic phenoxy ring (R) favoured CaV3.2 inhibition. Whilst the -CF3phenoxyanilide compounds exhibited a high potency for the CaV2.2 channel, their low CNS MPO scores and high lipophilicity were indicative of a reduced likelihood of crossing the blood-brain barrier (BBB) and suboptimal physicochemical characteristics. The outcomes of this investigation provided valuable insights into the development of selective calcium channel inhibitors for the treatment of neuropathic pain, while building on previous SAR studies performed within the research group.",

keywords = "Ca2.2, Ca3.2, N-type calcium channel, Pain, Phenoxyanilide, T-type calcium channel",

author = "Bispat, \{Anjie S.\} and Cardoso, \{Fernanda C.\} and Mahadhi Hasan and Adams, \{Callum E.\} and Lewis, \{Richard J.\} and Duggan, \{Peter J.\} and Tuck, \{Kellie L.\}",

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doi = "10.1016/j.bmc.2025.118449",

language = "English",

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journal = "Bioorganic and Medicinal Chemistry",

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T1 - Inhibition of N-type calcium channels by phenoxyanilide analogues

AU - Bispat, Anjie S.

AU - Cardoso, Fernanda C.

AU - Hasan, Mahadhi

AU - Adams, Callum E.

AU - Lewis, Richard J.

AU - Duggan, Peter J.

AU - Tuck, Kellie L.

PY - 2026/1/1

Y1 - 2026/1/1

N2 - A series of N,N-dimethylated phenoxyanilide analogues were synthesised and evaluated for their activity at CaV2.2 and CaV3.2 channels. The SAR study conducted, highlighted that steric and hydrophobic interactions primarily enhanced the affinity for the CaV2.2 channel, while an electron-rich aromatic phenoxy ring (R) favoured CaV3.2 inhibition. Whilst the -CF3phenoxyanilide compounds exhibited a high potency for the CaV2.2 channel, their low CNS MPO scores and high lipophilicity were indicative of a reduced likelihood of crossing the blood-brain barrier (BBB) and suboptimal physicochemical characteristics. The outcomes of this investigation provided valuable insights into the development of selective calcium channel inhibitors for the treatment of neuropathic pain, while building on previous SAR studies performed within the research group.

AB - A series of N,N-dimethylated phenoxyanilide analogues were synthesised and evaluated for their activity at CaV2.2 and CaV3.2 channels. The SAR study conducted, highlighted that steric and hydrophobic interactions primarily enhanced the affinity for the CaV2.2 channel, while an electron-rich aromatic phenoxy ring (R) favoured CaV3.2 inhibition. Whilst the -CF3phenoxyanilide compounds exhibited a high potency for the CaV2.2 channel, their low CNS MPO scores and high lipophilicity were indicative of a reduced likelihood of crossing the blood-brain barrier (BBB) and suboptimal physicochemical characteristics. The outcomes of this investigation provided valuable insights into the development of selective calcium channel inhibitors for the treatment of neuropathic pain, while building on previous SAR studies performed within the research group.

KW - Ca2.2

KW - Ca3.2

KW - N-type calcium channel

KW - Pain

KW - Phenoxyanilide

KW - T-type calcium channel

UR - https://www.scopus.com/pages/publications/105019977499

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DO - 10.1016/j.bmc.2025.118449

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VL - 132

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

M1 - 118449

ER -

Inhibition of N-type calcium channels by phenoxyanilide analogues

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Keywords

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