K_V4 channel complexes, also known as Shal-type K⁺ channels, are expressed in a variety of tissues, with particularly high levels in the brain and heart. These channels are the primary subunits that contribute to transient, voltage-dependent K⁺ currents in the nervous system and the heart¹. These complexes are composed of pore-forming voltage-gated α-subunits (Shal/K_V4) and at least two classes of auxiliary β-subunits- KChIPs (K⁺-Channel-Interacting-Proteins) and DPLPs (Dipeptidyl-Peptidase-Like-Proteins)².

(S)-Duloxetine hydrochloride is a high affinity K_V4.3 blocker and is also a competitive inhibitor of 5-HT and norepinephrine (NE) re-uptake. Duloxetine hydrochloride has an effective concentration of 1-300 μM with an IC₅₀ of 8.4 μM on cloned K_V4.3 channels.

Duloxetine is widely used for the treatment of Major Depressive Disorder (MDD) through the inhibition of 5-HT and NE re-uptake. Duloxetine is generally well tolerated by patients compared to other anti-depressants with relatively mild side-effects such as nausea, dry mouth and fatigue being the most common. Duloxetine is also used for other psychological conditions such as the treatment of general anxiety disorder (GAD)⁴ and stress related urinary incontinence where, according to one study, Duloxetine managed to increase the quality of life (I-QOL) of these patients far better than the placebo treatment⁵. In diabetic patients suffering from associated peripheral neuropathic pain, Duloxetine was found to alleviate a 24-hour average pain evaluated on an 11-point Likert scale⁶.