Novel KCNQ2/Q3 Agonists as Potential Therapeutics for Epilepsy and Neuropathic Pain

Abstract

Current drugs for the treatment of seizure disorders, although effective in many patients, still suffer from a number of failures and are not effective in some forms of resistant epilepsies. Historically, many of these drugs have multiple mechanisms of action including calcium and sodium channel blockade as well as GABAergic activity and thus a number of associated side effects. Modulation of the M-current through opening of KCNQ channels has been proposed as a way to attenuate neuroexcitability and have a therapeutic benefit for the treatment of seizure disorders. Therefore, as part of our program to identify new treatments for epilepsy, we set out to identify agonists of KCNQ channels. High throughput screening of our corporate collection led to the identification of 1, adamantane-1-carboxylic acid (3-methyl-3H-benzothiazol-2-ylidine) hydrazide, a potent KCNQ2/Q3 agonist. Herein, we describe the syntheses and structure-activity relationships of analogues of 1 as well as their in vivo activity in animal models of epilepsy and neuropathic pain.

Breaking barriers to novel analgesic drug development

“…Several voltage-gated sodium channels (Nav1.3 28,29 , Nav 1.7, and Nav 1.8 30–35 ), potassium channels (KCNQ), calcium channels (Cav 2.2) and hyperpolarization-activated cyclic nucleotide-modulated channel (HCN) have been implicated in the modulation of ectopic activity and membrane excitability in sensory neurons especially after peripheral nerve injury 36–39 . However, a direct relationship between such ectopic activity of primary sensory neurons with spontaneous pain is yet to be proven, mainly due to inconsistent results and the paucity of reliable preclinical models, although live cell imaging with genetically encoded activity reporters should change this.…”

“…The search for enhancers of potassium currents to inhibit pain signaling is relatively recent, but already it is evident that the general strategy may be promising 205,206 . So far, the most attention for this approach has been on Kv7 (KCNQ) family channels 36,207–209 , and several members of the “two-pore” (K2P) family of channels 198,210 . An alternative approach to small molecule enhancers of channel function is to attempt to correct the changes in potassium channel gene expression associated with pain 201 .…”

Noise-induced hearing loss: Neuropathic pain via Ntrk1 signaling

“…Gene expression of Ccl12 was significantly reduced at both 14 and 28 days post-exposure whereas only Il1β gene expression was significantly depressed at 28 days post-exposure. Ntrk1 , Kcnq3 and Oprd1 play important roles in neuropathic pain (Benbouzid et al, 2008; Dondio et al, 2001; Dost et al, 2004; Fritch et al, 2010; Ma et al, 2010; Shinoda et al, 2007; Ugolini et al, 2007) while Ccl12 , Tlr2 , and Il1β are involved in inflammation (Gundra et al, 2011; Mojsilovic-Petrovic et al, 2007; Niven et al, 2015; Oh et al, 2012; Yang et al, 2009). Ntrk1 also may be a part of a negative feedback loop linking neuropathic pain and inflammation.…”

The many faces of the adamantyl group in drug design

“…An adamantyl-based derivative or g-aminobutyric acid, structurally analogous to 1-(aminomethyl)cyclohexaneacetic acid (gabapentin), has also been studied as a potential anticonvulsant, although its mechanism of action is unclear [85]. More recently, adamantylbased benzothiazolylidene derivatives have been explored as KCNQ2/Q3 agonists as potential anticonvulsant agents [86].…”