Structure-activity relationship studies in a new series of 2-amino-N-phenylacetamide inhibitors of Slack potassium channels

Alshaima'a M Qunies; Nigam M Mishra; Brittany D Spitznagel; Yu Du; Valerie S Acuña; C David Weaver; Kyle A Emmitte

doi:10.1016/j.bmcl.2022.129013

Structure-activity relationship studies in a new series of 2-amino-N-phenylacetamide inhibitors of Slack potassium channels

Bioorg Med Chem Lett. 2022 Nov 15:76:129013. doi: 10.1016/j.bmcl.2022.129013. Epub 2022 Sep 29.

Authors

Alshaima'a M Qunies¹, Nigam M Mishra², Brittany D Spitznagel³, Yu Du⁴, Valerie S Acuña², C David Weaver⁴, Kyle A Emmitte⁵

Affiliations

¹ Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA; Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA.
² Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA.
³ Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
⁴ Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
⁵ Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA. Electronic address: [email protected].

Abstract

In this Letter we describe structure-activity relationship (SAR) studies conducted in five distinct regions of a new 2-amino-N-phenylacetamides series of Slack potassium channel inhibitors exemplified by recently disclosed high-throughput screening (HTS) hit VU0606170 (4). New analogs were screened in a thallium (Tl⁺) flux assay in HEK-293 cells stably expressing wild-type human (WT) Slack. Selected analogs were screened in Tl⁺ flux versus A934T Slack and other Slo family members Slick and Maxi-K and evaluated in whole-cell electrophysiology (EP) assays using an automated patch clamp system. Results revealed the series to have flat SAR with significant structural modifications resulting in a loss of Slack activity. More minor changes led to compounds with Slack activity and Slo family selectivity similar to the HTS hit.

Keywords: 2-Amino-N-phenylacetamide; EIMFS; K(Na)1.1; KCNT1; MMPSI; Slack; Slo2.2.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

HEK293 Cells
Humans
Nerve Tissue Proteins / metabolism
Potassium Channels*
Potassium Channels, Sodium-Activated
Structure-Activity Relationship
Thallium*

Substances

Nerve Tissue Proteins
Potassium Channels
Potassium Channels, Sodium-Activated
Thallium
VU0606170

Abstract

Publication types

MeSH terms

Substances

Grants and funding