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. 2024 Jan 9;15(2):215-220.
doi: 10.1021/acsmedchemlett.3c00452. eCollection 2024 Feb 8.

The Bis(1,2,3,4-tetrahydroisoquinoline) Alkaloids Cepharanthine and Berbamine Are Ligands of SK Channels

Romain Vitello  1 , Hossein Taouba  1 , Marine Derand  1 , Jean-François Liégeois  1
Affiliations

The Bis(1,2,3,4-tetrahydroisoquinoline) Alkaloids Cepharanthine and Berbamine Are Ligands of SK Channels

Romain Vitello et al. ACS Med Chem Lett. .

Abstract

Cepharanthine, a multitarget alkaloid which has recently been shown to be effective against SARS-Cov-2, and berbamine, an alkaloid characterized as a calcium channel blocker, both share key structural elements with known small conductance calcium-activated potassium (SK) channel blockers. These structural similarities led us to evaluate their affinity for SK channels. Therefore, we performed in vitro binding on SK2 and SK3 subtypes and highlighted micromolar to sub-micromolar affinities. Respectively, the Ki values on SK2 and SK3 are 1,318 μM and 1,091 μM for cepharanthine and 0,284 μM and 0,679 μM for berbamine. These newfound affinities correspond to the concentrations at which the alkaloids are found to be active against several pathologies. As SK interactions occur at the same levels as their therapeutic effects, there is a strong incentive to further investigate whether SK channels are involved in their pharmaceutical potency.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
3D structure and primary sequence of the 18 amino-acid peptide apamin, the reference ligand for the SK family. On the model, the carbon backbone is represented in green, the α helix is modeled in purple, and disulfide bridges are represented in yellow sticks. In the sequence, cysteines participating in disulfide bonds are highlighted in orange, and the disulfide bonds themselves are represented as connecting lines. The “RXCQ box”, the part of the structure responsible for interaction with SK channels according to current pharmacophore,, is underlined and highlighted in blue. The final amino acid, Histidine, highlighted in red, is amidated. It is also the labeling site of the radiolabeled apamine.
Figure 2
Figure 2
Chemical structures of previously investigated THIQ-derived SK blockers.
Figure 3
Figure 3
Chemical structures of the bis-THIQ alkaloids cepharanthine and berbamine. The THIQ moieties are highlighted in green in both compounds.
Figure 4
Figure 4
Binding competition curves obtained for the alkaloids on human SK2 channels (top) and on human SK3 channels (bottom) (n = 3 to 5, confer Table 1). Results are presented in comparison to apamin obtained in the same procedure (n = 4). The displacement of 125I-apamin, the radiolabeled ligand, is measured in relation to the competitor concentration (logarithmic). Curve points are means of the values from all experiments; standard deviation is represented by error bars.
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