Activation of Neuronal Voltage-Gated Potassium Kv7/KCNQ/M-Current by a Novel Channel Opener SCR2682 for Alleviation of Chronic Pain

Wang, Jing; Liu, Yani; Yang, Jiuyong; Guo, Xiaoyu; Hou, Xingming; Cao, Ju; Wang, Kewei

doi:10.1124/jpet.120.000357

Cited by 12 publications

(11 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… Other Kv7.2 channel openers like 71 , ICA-27243 ( 72 ), and SCR2682 ( 73 ) produced antinociception in rodent models of acute nociceptive pain (Figure ). − In addition, synergism was observed between 68 and morphine in an isobolographic analysis study using the formalin test …”

Section: Approaches To Develop Safer Ligands For New Pain Targetsmentioning

confidence: 98%

Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery

et al. 2021

View full text Add to dashboard Cite

Because of the problems associated with opioids, drug discovery efforts have been employed to develop opioids with reduced side effects using approaches such as biased opioid agonism, multifunctional opioids, and allosteric modulation of opioid receptors. Receptor targets such as adrenergic, cannabinoid, P2X3 and P2X7, NMDA, serotonin, and sigma, as well as ion channels like the voltage-gated sodium channels Nav1.7 and Nav1.8 have been targeted to develop novel analgesics. Several enzymes, such as soluble epoxide hydrolase, sepiapterin reductase, and MAGL/ FAAH, have also been targeted to develop novel analgesics. In this review, old and recent targets involved in pain signaling and compounds acting at these targets are summarized. In addition, strategies employed to reduce side effects, increase potency, and efficacy of opioids are also elaborated. This review should aid in propelling drug discovery efforts to discover novel analgesics.

show abstract

Section: Approaches To Develop Safer Ligands For New Pain Targetsmentioning

confidence: 98%

Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery

et al. 2021

View full text Add to dashboard Cite

show abstract

“…As such, a potential treatment for chronic pain can be increasing the function of such Kv7 channels in nociceptors. Retigabine, a Kv7 opener, was initially investigated as a potential seizure treatment but has been discontinued for concerns of toxicity and skin/retinal discoloration [ 109 , 110 , 111 ]. Recently, SCR2682 has been shown to decrease DRG neuron excitability in vitro and strongly activate Kv7 currents in neurons.…”

Section: Modulation Of Synaptic Plasticity By Kcnq Channelsmentioning

confidence: 99%

“…Additionally, future research into the ability of KCNQ modulators to treat other disorders related to dopaminergic pathways is another avenue that should be explored as well. Past studies have speculated that KCNQ openers, such as retigabine and ICA 27243, may be able to reduce the excitability of dopaminergic neurons in other tracts, such as the mesolimbic pathway, where overactivity results in schizophrenic symptoms [ 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 ]. This could be a potentially innovative tactic in clinical medicine as well, especially in the case of dementia-related psychosis, which is common onset among those with neurodegenerative disease.…”

Section: Kcnq Channels In Dopaminergic Motor Disordersmentioning

confidence: 99%

Behavior of KCNQ Channels in Neural Plasticity and Motor Disorders

et al. 2022

View full text Add to dashboard Cite

The broad distribution of voltage-gated potassium channels (VGKCs) in the human body makes them a critical component for the study of physiological and pathological function. Within the KCNQ family of VGKCs, these aqueous conduits serve an array of critical roles in homeostasis, especially in neural tissue. Moreover, the greater emphasis on genomic identification in the past century has led to a growth in literature on the role of the ion channels in pathological disease as well. Despite this, there is a need to consolidate the updated findings regarding both the pharmacotherapeutic and pathological roles of KCNQ channels, especially regarding neural plasticity and motor disorders which have the largest body of literature on this channel. Specifically, KCNQ channels serve a remarkable role in modulating the synaptic efficiency required to create appropriate plasticity in the brain. This role can serve as a foundation for clinical approaches to chronic pain. Additionally, KCNQ channels in motor disorders have been utilized as a direction for contemporary pharmacotherapeutic developments due to the muscarinic properties of this channel. The aim of this study is to provide a contemporary review of the behavior of these channels in neural plasticity and motor disorders. Upon review, the behavior of these channels is largely dependent on the physiological role that KCNQ modulatory factors (i.e., pharmacotherapeutic options) serve in pathological diseases.

show abstract

“…Both effects are reversed by M-channel inhibitor XE991. SCR 2682 also increases KCNQ2 mRNA and K v 7.2 protein expression in a rodent model of neuropathic pain (70) but its exact mechanism of action is yet to be determined. K v 7 thus retains its potential as a drug target for neuropathic pain (Table 1); chemical modification of the retigabine structure may provide new and effective therapeutic agents.…”

Section: Decreased Expression and Therapeutic Modulation Of K V 72/73 M-channelsmentioning

confidence: 99%

Section: Voltage-gated K + Channelsmentioning

confidence: 99%

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

Alles

Smith

2021

Front. Pain Res.

View full text Add to dashboard Cite

The persistence of increased excitability and spontaneous activity in injured peripheral neurons is imperative for the development and persistence of many forms of neuropathic pain. This aberrant activity involves increased activity and/or expression of voltage-gated Na+ and Ca2+ channels and hyperpolarization activated cyclic nucleotide gated (HCN) channels as well as decreased function of K+ channels. Because they display limited central side effects, peripherally restricted Na+ and Ca2+ channel blockers and K+ channel activators offer potential therapeutic approaches to pain management. This review outlines the current status and future therapeutic promise of peripherally acting channel modulators. Selective blockers of Nav1.3, Nav1.7, Nav1.8, Cav3.2, and HCN2 and activators of Kv7.2 abrogate signs of neuropathic pain in animal models. Unfortunately, their performance in the clinic has been disappointing; some substances fail to meet therapeutic end points whereas others produce dose-limiting side effects. Despite this, peripheral voltage-gated cation channels retain their promise as therapeutic targets. The way forward may include (i) further structural refinement of K+ channel activators such as retigabine and ASP0819 to improve selectivity and limit toxicity; use or modification of Na+ channel blockers such as vixotrigine, PF-05089771, A803467, PF-01247324, VX-150 or arachnid toxins such as Tap1a; the use of Ca2+ channel blockers such as TTA-P2, TTA-A2, Z 944, ACT709478, and CNCB-2; (ii) improving methods for assessing “pain” as opposed to nociception in rodent models; (iii) recognizing sex differences in pain etiology; (iv) tailoring of therapeutic approaches to meet the symptoms and etiology of pain in individual patients via quantitative sensory testing and other personalized medicine approaches; (v) targeting genetic and biochemical mechanisms controlling channel expression using anti-NGF antibodies such as tanezumab or re-purposed drugs such as vorinostat, a histone methyltransferase inhibitor used in the management of T-cell lymphoma, or cercosporamide a MNK 1/2 inhibitor used in treatment of rheumatoid arthritis; (vi) combination therapy using drugs that are selective for different channel types or regulatory processes; (vii) directing preclinical validation work toward the use of human or human-derived tissue samples; and (viii) application of molecular biological approaches such as clustered regularly interspaced short palindromic repeats (CRISPR) technology.

show abstract

Activation of Neuronal Voltage-Gated Potassium Kv7/KCNQ/M-Current by a Novel Channel Opener SCR2682 for Alleviation of Chronic Pain

Cited by 12 publications

References 43 publications

Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery

Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery

Behavior of KCNQ Channels in Neural Plasticity and Motor Disorders

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

Contact Info

Product

Resources

About