title: Chemical modifications of the N-methyl-laudanosine scaffold point to new directions for SK channels exploration.
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.
authors.affiliation: Laboratory of Medicinal Chemistry & C.I.R.M., University of Liège, avenue de l'Hôpital, 1 (B36), B-4000 Liège 1, Belgium; Laboratory of Pharmacology & GIGA-Neuroscience, University of Liège, avenue de l'Hôpital, 1 (B36), B-4000 Liège 1, Belgium.
authors.forename: Eduard
authors.initials: E
authors.lastname: Badarau
authors.affiliation: Laboratory of Medicinal Chemistry & C.I.R.M., University of Liège, avenue de l'Hôpital, 1 (B36), B-4000 Liège 1, Belgium; Laboratory of Pharmacology & GIGA-Neuroscience, University of Liège, avenue de l'Hôpital, 1 (B36), B-4000 Liège 1, Belgium.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dilly
authors.affiliation: Department of Chemistry, University of Namur, rue de Bruxelles, 61, B-5000 Namur, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.affiliation: Laboratory of Pharmacology & GIGA-Neuroscience, University of Liège, avenue de l'Hôpital, 1 (B36), B-4000 Liège 1, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Seutin
authors.affiliation: Laboratory of Medicinal Chemistry & C.I.R.M., University of Liège, avenue de l'Hôpital, 1 (B36), B-4000 Liège 1, Belgium. Electronic address: JF.Liegeois@ulg.ac.be.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Liégeois
mesh_terms: D000595:Amino Acid Sequence; D001030:Apamin / Q000737:chemistry; D001665:Binding Sites; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009584:Nitrogen / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines / Q000737:chemistry
chemical_list: D007546:Isoquinolines; C496897:KCNN2 protein, human; C406328:KCNN3 protein, human; D051640:Small-Conductance Calcium-Activated Potassium Channels; D044005:Tetrahydroisoquinolines; C465280:methyl-laudanosine; D001030:Apamin; D009584:Nitrogen
keywords: Apamin; Benzyloxy; Butanamide; Docking; Enantiomers; In vitro binding; Isoquinoline; Rational design; Small conductance calcium-activated K(+) channels