In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel

被引：9

作者：

Iraci, Nunzio ^{[1
]}

Carotenuto, Lidia ^{[2
]}

Ciaglia, Tania ^{[3
]}

Belperio, Giorgio ^{[5
]}

Di Matteo, Francesca ^{[3
]}

Mosca, Ilaria ^{[6
]}

Carleo, Giusy ^{[2
]}

Basilicata, Manuela Giovanna ^{[4
]}

Ambrosino, Paolo ^{[5
]}

Turcio, Rita ^{[3
]}

Puzo, Deborah ^{[6
]}

Pepe, Giacomo ^{[3
]}

Gomez-Monterrey, Isabel ^{[7
]}

Soldovieri, Maria Virginia ^{[6
]}

Di Sarno, Veronica ^{[3
]}

Campiglia, Pietro ^{[3
]}

Miceli, Francesco ^{[2
]}

Bertamino, Alessia ^{[3
]}

Ostacolo, Carmine ^{[3
]}

Taglialatela, Maurizio ^{[2
]}

机构：

[1] Univ Messina, Dept Chem Biol Pharmaceut & Environm Sci CHIBIOFAR, I-98166 Messina, Italy

[2] Univ Federico II Naples, Dept Neurosci Reprod Sci & Dent, I-80131 Naples, Italy

[3] Univ Salerno, Dept Pharm, I-84084 Fisciano, SA, Italy

[4] Univ Campania Luigi Vanvitelli, Dept Adv Med & Surg Sci, I-80138 Naples, Italy

[5] Univ Sannio, Dept Sci & Technol, I-82100 Benevento, Italy

[6] Univ Molise, Dept Med & Hlth Sci Vincenzo Tiberio, I-86100 Campobasso, Italy

[7] Univ Federico II Naples, Dept Pharm, I-80131 Naples, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 11期

关键词：

ACTIVATED POTASSIUM CHANNEL; MIGRATING PARTIAL SEIZURES; QT INTERVAL PROLONGATION; K+ CHANNELS; ACCURATE DOCKING; SENSORY NEURONS; SLACK; HERG; MUTATIONS; PROTEIN;

D O I：

10.1021/acs.jmedchem.4c00268

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Gain-of-function (GoF) variants in KCNT1 channels cause severe, drug-resistant forms of epilepsy. Quinidine is a known KCNT1 blocker, but its clinical use is limited due to severe drawbacks. To identify novel KCNT1 blockers, a homology model of human KCNT1 was built and used to screen an in-house library of compounds. Among the 20 molecules selected, five (CPK4, 13, 16, 18, and 20) showed strong KCNT1-blocking ability in an in vitro fluorescence-based assay. Patch-clamp experiments confirmed a higher KCNT1-blocking potency of these compounds when compared to quinidine, and their selectivity for KCNT1 over hERG and Kv7.2 channels. Among identified molecules, CPK20 displayed the highest metabolic stability; this compound also blocked KCNT2 currents, although with a lower potency, and counteracted GoF effects prompted by 2 recurrent epilepsy-causing KCNT1 variants (G288S and A934T). The present results provide solid rational basis for future design of novel compounds to counteract KCNT1-related neurological disorders.

引用

页码：9124 / 9149

页数：26

共 102 条

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