KCNT1 Channel Blockers: A Medicinal Chemistry Perspective

Francesca Di Matteo; Francesca Mancuso; Rita Turcio; Tania Ciaglia; Claudio Stagno; Carla Di Chio; Pietro Campiglia; Alessia Bertamino; Salvatore Vincenzo Giofrè; Carmine Ostacolo; Nunzio Iraci

doi:10.3390/molecules29122940

KCNT1 Channel Blockers: A Medicinal Chemistry Perspective

Molecules. 2024 Jun 20;29(12):2940. doi: 10.3390/molecules29122940.

Affiliations

¹ Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy.
² Department of Chemical, Biological, Pharmaceutical and Environmental Sciences (CHIBIOFARAM), University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy.

Abstract

Potassium channels have recently emerged as suitable target for the treatment of epileptic diseases. Among potassium channels, KCNT1 channels are the most widely characterized as responsible for several epileptic and developmental encephalopathies. Nevertheless, the medicinal chemistry of KCNT1 blockers is underdeveloped so far. In the present review, we describe and analyse the papers addressing the issue of KCNT1 blockers' development and identification, also evidencing the pros and the cons of the scientific approaches therein described. After a short introduction describing the epileptic diseases and the structure-function of potassium channels, we provide an extensive overview of the chemotypes described so far as KCNT1 blockers, and the scientific approaches used for their identification.

Keywords: KCNT1 blockers’ identification; KCNT1 potassium channel; epileptic encephalopathies; medicinal chemistry campaigns.

Publication types

Review

MeSH terms

Animals
Anticonvulsants / chemistry
Anticonvulsants / pharmacology
Anticonvulsants / therapeutic use
Chemistry, Pharmaceutical* / methods
Epilepsy* / drug therapy
Epilepsy* / metabolism
Humans
Nerve Tissue Proteins / antagonists & inhibitors
Nerve Tissue Proteins / chemistry
Nerve Tissue Proteins / metabolism
Potassium Channel Blockers* / chemistry
Potassium Channel Blockers* / pharmacology
Potassium Channel Blockers* / therapeutic use
Potassium Channels, Sodium-Activated
Potassium Channels, Tandem Pore Domain / antagonists & inhibitors
Potassium Channels, Tandem Pore Domain / chemistry
Potassium Channels, Tandem Pore Domain / metabolism
Potassium Channels, Voltage-Gated / antagonists & inhibitors
Potassium Channels, Voltage-Gated / metabolism
Structure-Activity Relationship

Substances

Potassium Channel Blockers
KCNT1 protein, human
Anticonvulsants
Nerve Tissue Proteins
Potassium Channels, Tandem Pore Domain
Potassium Channels, Voltage-Gated
Potassium Channels, Sodium-Activated

Grants and funding

C.O. and A.B. received funding from the Italian Ministry for University and Research in the frame of the Next Generation EU National Recovery and Resilience Plan (PRIN2022PNRR, project P2022YYTKF—Targeting rare epileptic encephalopathies: design and preclinical development of KCNT1 modulators—TELOS). C.O. received funding from the University of Salerno (FARB2023 project ORSA238219), and C.O. also received funding from the Regione Campania project, within PON FESR 2021–2027 fundings, with the project “Approcci innovativi allo studio di patogenesi, modelli, terapie e percorsi assistenziali in malattie rare neuropsichiatriche, neuromuscolari e sensoriali—NEURORARE”. N.I. and S.V.G. received funding from the University of Messina (FFABR Unime 2023).