An Anthrone-Based Kv7.2/7.3 Channel Blocker with Improved Properties for the Investigation of Psychiatric and Neurodegenerative Disorders

2019 ◽  
Author(s):  
Jacob Porter ◽  
Oscar Vivas-Rodriguez ◽  
C. David Weaver ◽  
Eamonn Dickson ◽  
Abdulmohsen Alsafran ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Neurodegenerative Disorders ◽  
Channel Blocker ◽  
Optimal Combination ◽  
Channel Blockers ◽  
Enolate Alkylation ◽  
Cyp Inhibition ◽  
Alkylation Reactions ◽  
Metabolic Instability

A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (JDP-107) with an optimal combination of potency (IC<sub>50</sub>= 0.16 𝜇M in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.

An Anthrone-Based Kv7.2/7.3 Channel Blocker with Improved Properties for the Investigation of Psychiatric and Neurodegenerative Disorders

2019 ◽  
Author(s):  
Jacob Porter ◽  
Oscar Vivas-Rodriguez ◽  
C. David Weaver ◽  
Eamonn Dickson ◽  
Abdulmohsen Alsafran ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Neurodegenerative Disorders ◽  
Channel Blocker ◽  
Optimal Combination ◽  
Channel Blockers ◽  
Enolate Alkylation ◽  
Cyp Inhibition ◽  
Alkylation Reactions ◽  
Metabolic Instability

A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (JDP-107) with an optimal combination of potency (IC<sub>50</sub>= 0.16 𝜇M in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.

Voltage Gated Sodium Channel Blockers: Synthesis of Mexiletine Analogues and Homologues

2020 ◽  
Vol 27 ◽  
Author(s):  
Alessia Catalano ◽  
Carlo Franchini ◽  
Alessia Carocci
Keyword(s):  
Sodium Channel ◽  
Channel Blocker ◽  
Parent Compound ◽  
Channel Blockers ◽  
Sodium Channel Blocker ◽  
Starting Point ◽  
Channel Blocking ◽  
Blocking Activity ◽  
Synthetic Routes ◽  
Lateral Sclerosis

: Mexiletine is an antiarrhythmic drug belonging to IB class, acting as sodium channel blocker. Besides its well-known activity on arrhythmias, its usefulness in the treatment of myotonia, myotonic distrophy and amyotrophic lateral sclerosis is now widely recognized. Nevertheless, it has been retired from the market in several countries because of its undesired effects. Thus, several papers were reported in the last years about analogues and homologues of mexiletine being endowed with a wider therapeutic ratio and a more selectivity of action. Some of them showed sodium channel blocking activity higher than the parent compound. It is noteworthy that mexiletine is used in therapy as a racemate even though a difference in the activities of the two enantiomers were widely demonstrated, with (–)-(R)-enantiomer being more active: this finding led several research groups to study mexiletine and its analogues and homologues in their optically active forms. This review summarizes the different synthetic routes used to obtain these compounds. They could represent an interesting starting point to new mexiletine-like compounds without common side effects related to the use of mexiletine.

Electroanalytical Methods for Determination of Calcium Channel Blockers

2019 ◽  
Vol 15 (3) ◽  
pp. 207-218 ◽  
Author(s):  
Fatma Ağın
Keyword(s):  
Calcium Channel ◽  
Calcium Channel Blockers ◽  
Channel Blocker ◽  
Heart Diseases ◽  
Dosage Forms ◽  
Channel Blockers ◽  
Electroanalytical Methods ◽  
Pharmaceutical Dosage Forms ◽  
Ischemic Heart Diseases

Background:Calcium Channel Blockers (CCBs) are widely used in the treatment of cardiovascular and ischemic heart diseases in recent years. They treat arrhythmias by reducing cardiac cycle contraction and also benefit ischemic heart diseases. Electroanalytical methods are very powerful analytical methods used in the pharmaceutical industry because of the determination of therapeutic agents and/or their metabolites in clinical samples at extremely low concentrations (10-50 ng/ml). The purpose of this review is to gather electroanalytical methods used for the determination of calcium channel blocker drugs in pharmaceutical dosage forms and biological media selected mainly from current articles.Methods:This review mainly includes recent determination studies of calcium channel blockers by electroanalytical methods from pharmaceutical dosage forms and biological samples. The studies of calcium channel blockers electroanalytical determination in the literature were reviewed and interpreted.Results:There are a lot of studies on amlodipine and nifedipine, but the number of studies on benidipine, cilnidipine, felodipine, isradipine, lercanidipine, lacidipine, levamlodipine, manidipine, nicardipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, diltiazem, and verapamil are limited in the literature. In these studies, DPV and SWV are the most used methods. The other methods were used less for the determination of calcium channel blocker drugs.Conclusion:Electroanalytical methods especially voltammetric methods supply reproducible and reliable results for the analysis of the analyte. These methods are simple, more sensitive, rapid and inexpensive compared to the usually used spectroscopic and chromatographic methods.

scholarly journals Ca2+-activated Cl− current in sheep lymphatic smooth muscle

2000 ◽  
Vol 279 (5) ◽  
pp. C1327-C1335 ◽  
Author(s):  
H. M. Toland ◽  
K. D. McCloskey ◽  
K. D. Thornbury ◽  
N. G. McHale ◽  
M. A. Hollywood
Keyword(s):  
Smooth Muscle ◽  
Carboxylic Acid ◽  
Patch Clamp ◽  
Action Potentials ◽  
Channel Blocker ◽  
Equilibrium Potential ◽  
Plateau Phase ◽  
Current Clamp ◽  
Patch Clamp Technique ◽  
Perforated Patch Clamp

Freshly dispersed sheep mesenteric lymphatic smooth muscle cells were studied at 37°C using the perforated patch-clamp technique with Cs+- and K+-filled pipettes. Depolarizing steps evoked currents that consisted ofl-type Ca2+ [ I Ca(L)] current and a slowly developing current. The slow current reversed at 1 ± 1.5 mV with symmetrical Cl− concentrations compared with 23.2 ± 1.2 mV ( n = 5) and −34.3 ± 3.5 mV ( n = 4) when external Cl− was substituted with either glutamate (86 mM) or I− (125 mM). Nifedipine (1 μM) blocked and BAY K 8644 enhanced I Ca(L), the slow-developing sustained current, and the tail current. The Cl− channel blocker anthracene-9-carboxylic acid (9-AC) reduced only the slowly developing inward and tail currents. Application of caffeine (10 mM) to voltage-clamped cells evoked currents that reversed close to the Cl− equilibrium potential and were sensitive to 9-AC. Small spontaneous transient depolarizations and larger action potentials were observed in current clamp, and these were blocked by 9-AC. Evoked action potentials were triphasic and had a prominent plateau phase that was selectively blocked by 9-AC. Similarly, fluid output was reduced by 9-AC in doubly cannulated segments of spontaneously pumping sheep lymphatics, suggesting that the Ca2+-activated Cl− current plays an important role in the electrical activity underlying spontaneous activity in this tissue.

Ionic channels in corneal endothelium

1996 ◽  
Vol 270 (4) ◽  
pp. C975-C989 ◽  
Author(s):  
J. L. Rae ◽  
M. A. Watsky
Keyword(s):  
Patch Clamp ◽  
Corneal Endothelium ◽  
Single Channel ◽  
Cell Voltage ◽  
Anion Channel ◽  
Ionic Channels ◽  
K Channel ◽  
Na Channel ◽  
Channel Blockers ◽  
K Currents

Single-channel patch-clamp techniques as well as standard and perforated-patch whole cell voltage-clamp techniques have been applied to the study of ionic channels in the corneal endothelium of several species. These studies have revealed two major K+ currents. One is due to an anion- and temperature-stimulated channel that is blocked by Cs+ but not by most other K+ channel blockers, and the other is similar to the family of A-currents found in excitable cells. The A-current is transient after a depolarizing voltage step and is blocked by both 4-aminopyridine and quinidine. These two currents are probably responsible for setting the -50 to -60 mV resting voltage reported for these cells. A Ca(2+)-activated ATP-inhibited nonselective cation channel and a tetrodotoxin-blocked Na+ channel are possible Na+ inflow pathways, but, given their gating properties, it is not certain that either channel works under physiological conditions. A large-conductance anion channel has also been identified by single-channel patch-clamp techniques. Single corneal endothelial cells have input resistances of 5-10 G omega and have steady-state K+ currents that are approximately 10 pA at the resting voltage. Pairs or monolayers of cells are electrically coupled and dye coupled through gap junctions.

scholarly journals L-type calcium channel blocker increases VEGF concentrations in retinal cells and human serum

2021 ◽  
Author(s):  
Anmol Kumar ◽  
Stefan Mutter ◽  
Erika Parente ◽  
Valma Harjutsalo ◽  
Raija Lithovius ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Human Serum ◽  
Channel Blocker ◽  
Channel Blockers ◽  
Vascular Endothelial ◽  
Retinal Cells ◽  
Diabetic Eye Disease ◽  
Design And Methods ◽  
Endothelial Growth Factor

Objective: Vascular endothelial growth factor (VEGF) plays a key role in diabetic retinopathy (DR). L-type calcium channel blockers (LTCCBs) have been widely used as antihypertensive medication (AHM), but their association with VEGF and DR is still unclear. Therefore, we explored the effect of LTCCBs compared to other AHMs on VEGF concentrations in retinal cells and human serum. Furthermore, we evaluated the association between the use of LTCCBs and the risk of severe diabetic eye disease (SDED). Research design and methods: Muller cells (MIO-M1) were cultured as per recommended protocol and treated with LTCCBs and other AHMs. VEGF secreted from cells were collected at 24 hours intervals. In an interventional study, 39 individuals received LTCCBs or other AHM for four weeks with a four-week wash-out placebo period between treatments. VEGF was measured during the medication and placebo periods. Finally, we evaluated the risk of SDED associated with LTCCB usage in 192 individuals from the FinnDiane Study in an oberservational setting. Results: In the cell cultures, medium VEGF concentration increased time-dependently after amlodipine (p<0.01) treatment, but not after losartan (p>0.01), or lisinopril (p>0.01). Amlodipine, but no other AHM, increased serum VEGF concentration (p<0.05) during the interventional clinical study. The usage of LTCCB was not associated with the risk of SDED in the observational study. Conclusions: LTCCB increases VEGF concentrations in retinal cells and human serum. However, the usage of LTCCBs does not appear to be associated with SDED in adults with type 1 diabetes.

Rat Prl and TSH secretion are regulated differently by K(+)-channel blockers

1994 ◽  
Vol 266 (1) ◽  
pp. E39-E43 ◽  
Author(s):  
X. Wang ◽  
T. Inukai ◽  
M. A. Greer ◽  
S. E. Greer
Keyword(s):  
Channel Blocker ◽  
Cell Types ◽  
Inhibitory Effect ◽  
Thyroid Stimulating Hormone ◽  
K Channel ◽  
Channel Blockers ◽  
Pituitary Cells ◽  
Dependent Manner ◽  
K Channels ◽  
Tsh Secretion

All four different K(+)-channel blockers [tetraethylammonium (TEA), a nonselective K(+)-channel blocker; tolbutamide, an ATP-sensitive K(+)-channel blocker; quinine and 4-aminopyridine, both primarily voltage-dependent K(+)-channel blockers] stimulated prolactin (Prl) secretion by acutely dispersed anterior pituitary cells but had no effect on thyroid-stimulating hormone (TSH) secretion. TEA stimulated Prl secretion in a dose-dependent manner between 1 microM and 20 mM, but even as high as 20 mM, TEA did not induce TSH secretion. Valinomycin (2 microM), a K+ ionophore, inhibited both basal and TEA-induced Prl secretion. TEA-stimulated Prl secretion was abolished by using a Ca(2+)-depleted medium or adding 10 microM dopamine. TEA did not reverse the inhibitory effect of dopamine on thyrotropin-releasing hormone-induced Prl secretion. Our data indicate that K+ channels may play a role in the secretion of adenohypophysial hormones that is idiosyncratic for each hormone. Differences in the role of K+ channels may reflect differences between the various pituitary cell types in plasma membrane ion channel composition, membrane potential, or the mechanism of exocytosis.

Role of K+ channels in adrenal catecholamine secretion in anesthetized dogs

1998 ◽  
Vol 274 (4) ◽  
pp. R1125-R1130 ◽  
Author(s):  
Takahiro Nagayama ◽  
Kimiya Masada ◽  
Makoto Yoshida ◽  
Mizue Suzuki-Kusaba ◽  
Hiroaki Hisa ◽  
...  
Keyword(s):  
Channel Blocker ◽  
Splanchnic Nerve ◽  
Channel Blockers ◽  
Cholinergic Agonists ◽  
Voltage Dependent ◽  
Anesthetized Dogs ◽  
Splanchnic Nerve Stimulation ◽  
Mast Cell Degranulating ◽  
Small Conductance

We examined the role of K+ channels in the secretion of adrenal catecholamine (CA) in response to splanchnic nerve stimulation (SNS), acetylcholine (ACh), 1,1-dimethyl-4-phenyl-piperazinium (DMPP), and muscarine in anesthetized dogs. K+ channel blockers and the cholinergic agonists were infused and injected, respectively, into the adrenal gland. The voltage-dependent K+ channel (KA type) blocker mast cell degranulating (MCD) peptide infusion (10–100 ng/min) enhanced increases in CA output induced by SNS (1–3 Hz), but it did not affect increases in CA output induced by ACh (0.75–3 μg), DMPP (0.1–0.4 μg), or muscarine (0.5–2 μg). The small-conductance Ca2+-activated K+(SKCa) channel blocker scyllatoxin infusion (10–100 ng/min) enhanced the ACh-, DMPP-, and muscarine-induced increases in CA output, but it did not affect the SNS-induced increases in CA output. These results suggest that KA channels may play an inhibitory role in the regulation of adrenal CA secretion in response to SNS and that SKCa channels may play the same role in the secretion in response to exogenously applied cholinergic agonists.

Calcium channel blockers inhibit endogenous pyrogen fever in rats and rabbits

1991 ◽  
Vol 71 (3) ◽  
pp. 951-955 ◽  
Author(s):  
J. T. Stitt ◽  
S. G. Shimada
Keyword(s):  
Channel Blocker ◽  
Standard Dose ◽  
Detectable Effect ◽  
Prostaglandin E ◽  
Channel Blockers ◽  
Sprague Dawley ◽  
Endogenous Pyrogen ◽  
Ambient Temperatures ◽  
Antipyretic Activity ◽  
Sprague Dawley Rats

We have previously shown that febrile responses in both rats and rabbits are elicited by the intravenous injection of a semipurified endogenous pyrogen (EP) prepared from human monocytes. We are now presenting evidence that these febrile responses are mediated via activation of Ca2+ channels by EP. The febrile responses of male New Zealand White rabbits and Sprague-Dawley rats to a standard dose of EP were determined at their respective thermoneutral ambient temperatures. The animals were then treated with Ca2+ channel blocker verapamil (7.5 mg/kg iv) 30–60 min before the EP challenge. In every case the febrile response to EP was markedly attenuated after verapamil pretreatment, while administration of verapamil by itself had no detectable effect on body temperature. Another Ca2+ channel blocker, nifedipine (5 mg/kg iv), was shown to possess antipyretic activity in rats also. To localize where in the fever pathway these Ca2+ channel blockers were acting, we investigated the effect of verapamil at the same dose on fevers that were produced by microinjection of prostaglandin E (PGE) directly into the brain. These PGE fevers were unaffected by verapamil pretreatment, indicating that the antipyretic action of Ca2+ channel blockers occurs before the formation of PGE in response to EP stimulation. The most likely locus of action is the activation of the enzyme phospholipase A2, which regulates the production of arachidonic acid from cellular phospholipids in the prostanoid cascade.

Influence of Nifedipine on the Visual Fields of Patients with Optic-Nerve-Head Diseases

1994 ◽  
Vol 4 (1) ◽  
pp. 24-28 ◽  
Author(s):  
A.Z. Gaspar ◽  
J. Flammer ◽  
PH. Hendrickson
Keyword(s):  
Optic Nerve ◽  
Visual Field ◽  
Calcium Channel ◽  
Calcium Channel Blocker ◽  
Optic Nerve Head ◽  
Channel Blocker ◽  
Glaucoma Patient ◽  
Visual Fields ◽  
Visual Field Defects ◽  
Channel Blockers

Calcium-channel blockers have long been employed in coronary disease, and recent investigations have indicated their efficacy in improving the visual field in low-tension glaucoma or presumed vasospasm, possibly by enhancing ocular circulation. We evaluated the short-term influence of a typical calcium-channel blocker, nifedipine, on 59 patients with visual-field defects, some with optic-nerve-head pathology (n = 38) and some with normal-appearing optic nerve heads (n = 21). On the average, a statistically significant improvement of 1.2 dB was observed. Different types of patients, however, behaved quite differently. The younger the patient, the greater the improvement. Patients with normal optic nerve heads improved by 1.54 dB, whereas patients with optic-nerve-head excavation improved by only 0.66 dB. No response was observed in patients with anterior ischemic neuropathy. Marked deterioration was noted in one glaucoma patient with low systemic blood pressure. The visual-field changes were observed in the scotomatous and non-scotomatous areas. Thus, the calcium-channel blocker nifedipine can be effective in some selected diseases whose pathogenesis probably involves vascular dysregulation though it may even be contraindicated in others

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