Design, synthesis, and characterization of BK channel openers based on oximation of abietane diterpene derivatives

Stereochemical evidence for stabilization of a nitrogen cation by neighboring chlorine or bromine

“…In the course of our development of potassium ion channel openers (16,17), we encountered unusual regioselectivity in the trifluoroacetic acid (TFA)-catalyzed Beckmann rearrangement of oximes of 7-oxo-dehydroabietic acid derivatives ( Table 1). The parent O-Ts-oxime of methyl 7-oxo-dehydroabietate 2a provides exclusively a benzene migration lactam 3a in TFA at 20°C (i.e., the nitrogen atom is inserted into the C oxime -C aromatic bond).…”

Molecular Mechanisms of Resin Acids and Their Derivatives on the Opening of a Potassium Channel

“…Small modifications of the molecular structure (such as alterations in chirality) can have a large impact on the G(V) shifting propensity, indicating that it might be possible to design compounds with selectivity for specific ion channels. Some resin acids and their derivatives also target the calcium-and voltage-sensitive BK channel (Imaizumi 2002, Ohwada et al 2003, Tashima et al 2006, Cui et al 2008a, Cui et al 2008b, Cui et al 2010, Gessner et al 2012, Ido et al 2013, Cui et al 2016). Some, ion-channel selectivity is supported by the finding that Wu40, one of the most potent BK-channel opener (Ohwada et al 2003), only act as an average Shaker Kv channel opener (Paper II).…”

The smooth muscle-type β1subunit potentiates activation by DiBAC4(3) in recombinant BK channels

“…[23][24][25][26][27][28] In particular, a channel-opening compound with subunit specificity is relevant for cardiovascular physiology, where the β 1 subunit is predominant and acts as a molecular tuner critical to vasoregulation. 29 The importance of subunit specificity of channel activators extends to other fields, as well, because of the tissuespecific distribution of β subunits (i.e., β 4 in nervous system).…”