Abstract :
[en] Small conductance Ca2+-activated K+ (SK) channels play a role in modulating the firing rate and the firing pattern of neurons [Waroux, Eur J Neurosci, 2005, 22, 3111]. A blockade of these targets could be useful for the treatment of cognitive dysfunction, neuronal hyperexcitability or dopamine related disorders [Liégeois, Curr Med Chem, 2003, 10, 625]. At the peripheral level, the inhibition of these channels was demonstrated to prevent and terminate atrial fibrillation [Diness, Circ Arrhythm Electrophysiol, 2010, 3, 380]. Moreover, SK channels might represent potential targets for a new class of anticancer agents due to their involvement in breast cancer cell migration [Potier, Mol Cancer Ther, 2006, 5, 2946].
So far, available blockers are not suitable CNS pharmacological tools being either peptides or small molecules with permanent positive charges [Liégeois, Curr Med Chem, 2003, 10, 625; Graulich, J Med Chem, 2007, 50, 5070; Badarau, Bioorg Med Chem Lett, 2011, 21, 6756]. Therefore, symmetrical bis-isoquinolinium compounds have subsequently been transformed to 1,2,3,4-tetrahydroisoquinoline analogues by using sodium borohydride leading to a diastereoisomeric mixture (figure 1) in order to obtain potential CNS-penetrating agents [Graulich, Bioorg Med Chem Lett, 2008, 18, 3440; Neny, Proceedings of the 12th International Conference on In Vivo Methods, Vancouver, Canada, 2008, 267; Koulchitsky, Acta Physiologica, 2009, 195, 670]. Resolution of these mixtures and characterization of the corresponding stereoisomers [Wouters, Eur J Med Chem, 2010, 45, 3240] are necessary before further biological evaluation. In a series of 8- isopropyl analogues, chiral resolution failed for the analogues with propyl and m-xylyl linkers since two and one peaks, respectively, were detected [Nistor, J Pharm Biomed Anal, 2013, 74, 273]. Could these results be explained by an ineffective resolution or would another phenomenon be involved?
Further analysis using chiral chromatography, mass spectroscopy and circular dichroism of a sample of the propyl analogue revealed that it is a racemic mixture. X-ray cristallography and conformational analysis indicated a folded conformation of the propyl and m-xylyl analogues (figure 2) responsible for a stereoselective attack of the borohydride reagent during the reduction step. Additional 1H-NMR investigations support structural features detected by theoretical analysis.
