Ion Channels as Drug Targets in Central Nervous System Disorders

Waszkielewicz, Anna M.; Gunia, Agnieszka; Szkaradek, Natalia; Słoczyńska, Karolina; Krupinska, S.; Marona, Henryk

doi:10.2174/0929867311320100005

Cited by 85 publications

(55 citation statements)

References 357 publications

(324 reference statements)

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“…R f = 0.64 (1:9 MeOH/CH 2 Cl 2 ). 1 3 Br with silver triflate (AgOTf) column was passed into the reaction vial at RT, until radioactivity reached a maximum (~2 min), and then the reaction vial was isolated and heated at 80  C for 3 min. The contents of the reaction vial were diluted with NaHCO 3 solution (0.1 M, 1 mL), and injected onto the semi-preparative RP HPLC column with 3 mL injection loop for purification.…”

Section: H) Ms (Esi): 308 ([M-h] - 1%) (H)mentioning

confidence: 99%

“…It is found in the immune, peripheral, and central nervous systems; implicated in ATP-mediated cell death, regulation of receptor trafficking and inflammation; and associated with various cancer, neurological and cardiovascular disorders. [1][2][3][4] Neuroinflammation is considered to play an important role in a variety of neuropathologies, such as Alzheimer's disease, Parkinson's disease and traumatic brain injury. [5][6][7] P2X 7 receptor antagonists have been developed as potential pharmaceuticals for the treatment of various diseases including neuroinflammation.…”

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confidence: 99%

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Synthesis of [11C]GSK1482160 as a new PET agent for targeting P2X7 receptor

Gao

Wang

Green

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Abstract-The authentic standards GSK1482160 and its isomer, as well as the radiolabeling precursors desmethyl-GSK1482160 and Boc-protected desmethyl-GSK1482160 were synthesized from L-pyroglutamic acid, methyl L-pyroglutamate and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 27-28% in 3 steps, 58% in 4 steps, 76% in 1 step and 33% in 2 steps, respectively. [11 C]GSK1482160 was prepared from either desmethyl-GSK1482160 or Boc-protected desmethyl-GSK1482160 with [11 C]CH 3 OTf through N-[ 11 C]methylation and isolated by HPLC combined with SPE in 40-50% and 30-40% radiochemical yield, respectively, based on [ 11 C]CO 2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity at EOB was 370-1110 GBq/mol with a total synthesis time of ~40-minutes from EOB.

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Section: H) Ms (Esi): 308 ([M-h] - 1%) (H)mentioning

confidence: 99%

mentioning

confidence: 99%

Synthesis of [11C]GSK1482160 as a new PET agent for targeting P2X7 receptor

Gao

Wang

Green

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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“…Most AEDs have been designed to target ion channels and transporters and one that affects synaptic vesicle protein Sv2a with a goal to favor inhibition of over excitation and thereby decrease or prevent seizure activity/frequency (11–13). These include AEDs targeting voltage-gated sodium channels, voltage-gated calcium channels, voltage-gated potassium channels, the GABA system and receptor agonists, glutamate receptor antagonists, and other inhibitory neurotransmitters.…”

Section: Defects In Ionic Channels Cause Seizuresmentioning

confidence: 99%

Pore-Forming Proteins as Mediators of Novel Epigenetic Mechanism of Epilepsy

et al. 2017

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Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. In the last two decades, numerous gene defects underlying different forms of epilepsy have been identified with most of these genes encoding ion channel proteins. Despite these developments, the etiology of majority of non-familial epilepsies has no known associated genetic mutations and cannot be explained by defects in identified ion channels alone. We hypothesize that de novo formation of ion channels by naturally unfolded proteins (NUPs) increases neuronal excitability. Altered ionic homeostasis may initiate/contribute to cellular cascades related to epileptogenesis in susceptible individuals. Here, we consider two small proteins, namely, α-synuclein and stefin B, as prototypical candidates to illustrate the underlying mechanism(s). Previous work points to an association between epilepsy and α-synuclein or stefin B, but the mechanism(s) underlying such association remains elusive. We review the evidence to link the structure–function of these proteins with disease processes. Epigenetic mechanisms unrelated to altered DNA sequence(s) that may affect epileptogenesis include transcriptional or posttranscriptional regulation. Such epigenetic mechanisms or their combination(s) enhance the levels of these proteins and as a result the ability to form annular structures, which upon incorporation into membrane form novel ion channels and disturb intracellular ion homeostasis. Alternative epigenetic mechanisms may change amyloidogenic proteins by posttranslational modifications, thereby increasing their propensity to form channels. Further research elucidating the details about the formation of ion channels through these mechanisms and their role in epileptogenesis may define new molecular targets and guide the development of new drug targets.

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“…Ion channels are strikingly and commonly related to the new drug discovery process (Waszkielewicz et al, 2013). Subtype specific modulation of calcium channels, for example, has emerged as a new strategy for pain control (Bowersox et al, 1996;Staats et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the antinociceptive effect of PhTx3-4, a toxin from Phoneutria nigriventer , in models of thermal, chemical and incisional pain in mice

Silva

Castro

Oliveira

et al. 2015

Toxicon

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Venom-derived peptides constitute a unique source of drug prototypes for the pain management. Many of them can modulate voltage-gated calcium channels that are central in the processing of pain sensation. PhTx3-4 is a peptide isolated from Phoneutria nigriventer venom, which blocks high voltage-activated calcium channels with low specificity, thereby leading to neuroprotection in models of ischemia in vitro. The aim of the present work was evaluating the potential of intrathecal PhTx3-4 in the reversal of different nociceptive states in mice, furthermore assessing the potential of PhTx3-4 in triggering motor side effects. We found that bellow 100 pmol/site, PhTx3-4 did not cause major motor side effects. By comparison, ω-conotoxin MVIIA and ω-conotoxin MVIIC triggered motor side effects at the doses of 10 and 100 pmol/site, respectively. Also, PhTx3-4 (30 pmol/site) caused no significant alterations in the forced locomotor activity test (rotarod) and in the exploratory activity test (versamax). In a model of inflammatory persistent pain (formalin test), PhTx3-4 reversed nociceptive behavior both pre or post-administered, although this effect was observed only at the inflammatory phase of the test and not at the neurogenic phase. Comparatively, ω-conotoxin MVIIC was effective only when post-administered in the formalin test. Nonetheless, PhTx3-4 treatment was devoid of action in acute nociceptive thermal model (hotplate test), whereas morphine showed efficacy in this test. Efficacy of PhTx3-4 in the formalin test was associated with inhibition of formalin-induced glutamate release in the cerebrospinal fluid. PhTx3-4, but not ω-conotoxin MVIIC, reversed NMDA-induced nociceptive behavior indicating a putative role of PhTx3-4 at ionotropic glutamate receptors. Finally, we observed efficacy of PhTx3-4 in ameliorating mechanical hypersensitivity induced by paw incision, a post-operative and more clinically relevant pain model. Taken together, our data show that PhTx3-4 possesses antinociceptive effect in different models of pain in mice, suggesting that this toxin may serve as drug prototype for pain control.

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Ion Channels as Drug Targets in Central Nervous System Disorders

Cited by 85 publications

References 357 publications

Synthesis of [11C]GSK1482160 as a new PET agent for targeting P2X7 receptor

Synthesis of [11C]GSK1482160 as a new PET agent for targeting P2X7 receptor

Pore-Forming Proteins as Mediators of Novel Epigenetic Mechanism of Epilepsy

Characterization of the antinociceptive effect of PhTx3-4, a toxin from Phoneutria nigriventer , in models of thermal, chemical and incisional pain in mice

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