Medicinal Chemistry of Ca 2+ ‐activated K + Channel Modulators

Synthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels

10.26434/chemrxiv.5908276.v1 ◽

2018 ◽

Author(s):

Chris Dockendorff ◽

Disha M. Gandhi ◽

Ian H. Kimball ◽

Kenneth S. Eum ◽

Radda Rusinova ◽

...

Keyword(s):

Lipid Bilayer ◽

Lipid Bilayers ◽

Medicinal Chemistry ◽

K Channel ◽

Channel Activity ◽

Synthetic Analogs ◽

Voltage Gated ◽

Protein Ligand Interactions ◽

Membrane Perturbation ◽

Ligand Interactions

Distinguishing membrane perturbation from more direct protein-ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogs. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogs and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported.

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Synthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels

10.26434/chemrxiv.5908276 ◽

2018 ◽

Author(s):

Chris Dockendorff ◽

Disha M. Gandhi ◽

Ian H. Kimball ◽

Kenneth S. Eum ◽

Radda Rusinova ◽

...

Keyword(s):

Lipid Bilayer ◽

Lipid Bilayers ◽

Medicinal Chemistry ◽

K Channel ◽

Channel Activity ◽

Synthetic Analogs ◽

Voltage Gated ◽

Protein Ligand Interactions ◽

Membrane Perturbation ◽

Ligand Interactions

Distinguishing membrane perturbation from more direct protein-ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogs. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogs and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported.

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Medicinal Chemistry of Potassium Channel Modulators: An Update of Recent Progress (2011-2017)

Current Medicinal Chemistry ◽

10.2174/0929867325666180430152023 ◽

2019 ◽

Vol 26 (12) ◽

pp. 2062-2084 ◽

Cited By ~ 3

Author(s):

Vivek K. Vyas ◽

Palak Parikh ◽

Jonali Ramani ◽

Manjunath Ghate

Keyword(s):

Potassium Channels ◽

Potassium Channel ◽

Small Molecule ◽

Medicinal Chemistry ◽

Hormone Secretion ◽

K Channel ◽

Biological Functions ◽

Chemistry Research ◽

Channel Inhibition ◽

Potassium Channel Modulators

Background: Potassium (K+) channels participate in many physiological processes, cardiac function, cell proliferation, neuronal signaling, muscle contractility, immune function, hormone secretion, osmotic pressure, changes in gene expression, and are involved in critical biological functions, and in a variety of diseases. Potassium channels represent a large family of tetrameric membrane proteins. Potassium channels activation reduces excitability, whereas channel inhibition increases excitability. Objective: Small molecule K+ channel activators and inhibitors interact with voltage-gated, inward rectifying, and two-pore tandem potassium channels. Due to their involvement in biological functions, and in a variety of diseases, small molecules as potassium channel modulators have received great scientific attention. Methods: : In this review, we have compiled the literature, patents and patent applications (2011 to 2017) related to different chemical classes of potassium channel openers and blockers as therapeutic agents for the treatment of various diseases. Many different chemical classes of selective small molecule have emerged as potassium channel modulators over the past years. Conclusion: This review discussed the current understanding of medicinal chemistry research in the field of potassium channel modulators to update the key advances in this field.

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