Chemical modifications of the N-methyl-laudanosine scaffold point to new directions for SK channels exploration

Eduard Badarau, Sébastien Dilly, Johan Wouters, Vincent Seutin, Jean François Liégeois

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Abstract

An asparagine or a histidine are present in a similar position in the outer pore region of SK2 and SK3 channels, respectively. Therefore, this structural difference was targeted in order to develop selective blockers of SK channel subtypes. Following docking investigations, based on theoretical models of truncated SK2 and SK3 channels, the benzyl side chain of N-methyl-laudanosine (NML) was functionalized in order to target this specific amino-acid residues. Chiral butanamide and benzyloxy analogues were prepared, resolved and tested for their affinity for SK2 and SK3 channels. Isoquinolinium (NMIQ) derivatives have a higher affinity for both SK channel subtypes than the corresponding derivative with no functionalized side chain. This trend was observed also for the 1,2,3,4-tetrahydroisoquinoline (THIQ) analogues. A benzyloxy functionalized NML enantiomer has a higher affinity than NML stereoisomers. Otherwise, the conserved affinity of these analogues led to the opportunity to further investigate in terms of possible labeling for in vivo investigations of the role of SK channels.

Original languageEnglish
Pages (from-to)5616-5620
Number of pages5
JournalBioorganic & Medicinal Chemistry Letters
Volume24
Issue number24
DOIs
Publication statusPublished - 15 Dec 2014

Fingerprint

Chemical modification
Scaffolds
Derivatives
Stereoisomerism
Enantiomers
Asparagine
Histidine
Labeling
Theoretical Models
Amino Acids
Direction compound
methyl-laudanosine

Keywords

  • Apamin
  • Benzyloxy
  • Butanamide
  • channels
  • Docking
  • Enantiomers
  • In vitro binding
  • Isoquinoline
  • Rational design
  • Small conductance calcium-activated K

Cite this

Badarau, Eduard ; Dilly, Sébastien ; Wouters, Johan ; Seutin, Vincent ; Liégeois, Jean François. / Chemical modifications of the N-methyl-laudanosine scaffold point to new directions for SK channels exploration. In: Bioorganic & Medicinal Chemistry Letters. 2014 ; Vol. 24, No. 24. pp. 5616-5620.
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Chemical modifications of the N-methyl-laudanosine scaffold point to new directions for SK channels exploration. / Badarau, Eduard; Dilly, Sébastien; Wouters, Johan; Seutin, Vincent; Liégeois, Jean François.

In: Bioorganic & Medicinal Chemistry Letters, Vol. 24, No. 24, 15.12.2014, p. 5616-5620.

Research output: Contribution to journalArticle

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