Structure/Activity Analysis of TASK-3 Channel Antagonists Based on a 5,6,7,8 tetrahydropyrido[4,3-d]pyrimidine.

David Ramírez,Aytug K Kiper,Erix W Hernández-Rodríguez,Niels Decher,Samuel Morales-Navarro,Francisco V Sepúlveda,Susanne Rinné,Wendy González,Mauricio Bedoya

doi:10.3390/ijms20092252

Abstract

TASK-3 potassium (K+) channels are highly expressed in the central nervous system, regulating the membrane potential of excitable cells. TASK-3 is involved in neurotransmitter action and has been identified as an oncogenic K+ channel. For this reason, the understanding of the action mechanism of pharmacological modulators of these channels is essential to obtain new therapeutic strategies. In this study we describe the binding mode of the potent antagonist PK-THPP into the TASK-3 channel. PK-THPP blocks TASK-1, the closest relative channel of TASK-3, with almost nine-times less potency. Our results confirm that the binding is influenced by the fenestrations state of TASK-3 channels and occurs when they are open. The binding is mainly governed by hydrophobic contacts between the blocker and the residues of the binding site. These interactions occur not only for PK-THPP, but also for the antagonist series based on 5,6,7,8 tetrahydropyrido[4,3-d]pyrimidine scaffold (THPP series). However, the marked difference in the potency of THPP series compounds such as 20b, 21, 22 and 23 (PK-THPP) respect to compounds such as 17b, inhibiting TASK-3 channels in the micromolar range is due to the presence of a hydrogen bond acceptor group that can establish interactions with the threonines of the selectivity filter.

Highlights

Two-pore domain potassium (K2P) channels have been widely studied since the KCNK gene family was discovered [1], providing important advances in the understanding of their physiological roles
TASK-3 channels were identified as members of the K2P channel family and characterized by Kim et al [30]
Drug design targeting TASK-3 channels has increased over the years due to their wide expression in central nervous system, their role in several pathological conditions [31], and their overexpression in different cancer types such as breast, gastrointestinal tract, lung and melanoma [32]

Summary

Introduction

Two-pore domain potassium (K2P) channels have been widely studied since the KCNK gene family (encoding these proteins) was discovered [1], providing important advances in the understanding of their physiological roles. The TASK (TWIK-related acid-sensitive K+) channel subfamily includes three members (TASK-1, -3 and -5) [2]. Near to the center of the membrane, the M2 transmembrane segment is kinked by approximately 20◦, generating two lateral cavities (fenestrations) that connect the inner pore with the membrane [12]. These fenestrations have an essential role in the modulation of K2P channels [13,14] acting as binding pockets for drugs like norfluoxetine, the active metabolite of Prozac®, [10] or BL1249 [15] in TREK-2

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Conclusion