A Cucurbit[8]uril-Based Supramolecular Framework Material for Reversible Iodine Capture in the Vapor Phase and Solution.

The safe and efficient management of hazardous radioactive iodine is significant for nuclear waste reprocessing and environmental industries. A novel supramolecular framework compound based on cucurbit[8]uril (Q[8]) and 4-aminopyridine (4-AP) is reported in this paper. In the single crystal structure of Q[8]-(4-AP), two 4-AP molecules interact with the outer surface of Q[8] and the two other 4-AP molecules are encapsulated into the Q[8] cavity to form the self-assembly Q[8]-(4-AP). Iodine adsorption experiments show that the as-prepared Q[8]-(4-AP) not only has a high adsorption capacity (1.74 g· g-1) for iodine vapor but also can remove the iodine in the organic solvent and the aqueous solution with the removal efficiencies of 95% and 91%, respectively. The presence of a large number of hydrogen bonds between the iodine molecule and the absorbent, as seen in the single crystal structure of iodine-loaded Q[8]-(4-AP) (I2@Q[8]-(4-AP)), is thought to be responsible for the exceptional iodine adsorption capacity of the material. In addition, the adsorption-desorption tests reveal that the self-assembly material has no significant loss of iodine capture capacity after five cycles, indicating that it has sufficient reusability.

GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response.

Ataxia due to an autosomal dominant intronic GAA repeat expansion in FGF14 [GAA-FGF14 ataxia, spinocerebellar ataxia 27B (SCA27B)] has recently been identified as one of the most common genetic late-onset ataxias. We here aimed to characterize its phenotypic profile, natural history progression, and 4-aminopyridine (4-AP) treatment response. We conducted a multi-modal cohort study of 50 GAA-FGF14 patients, comprising in-depth phenotyping, cross-sectional and longitudinal progression data (up to 7 years), MRI findings, serum neurofilament light (sNfL) levels, neuropathology, and 4-AP treatment response data, including a series of n-of-1 treatment studies. GAA-FGF14 ataxia consistently presented as late-onset [60.0 years (53.5-68.5), median (interquartile range)] pancerebellar syndrome, partly combined with afferent sensory deficits (55%) and dysautonomia (28%). Dysautonomia increased with duration while cognitive impairment remained infrequent, even in advanced stages. Cross-sectional and longitudinal assessments consistently indicated mild progression of ataxia [0.29 Scale for the Assessment and Rating of Ataxia (SARA) points/year], not exceeding a moderate disease severity even in advanced stages (maximum SARA score: 18 points). Functional impairment increased relatively slowly (unilateral mobility aids after 8 years in 50% of patients). Corresponding to slow progression and low extra-cerebellar involvement, sNfL was not increased relative to controls. Concurrent second diseases (including progressive supranuclear palsy neuropathology) represented major individual aggravators of disease severity, constituting important caveats for planning future GAA-FGF14 trials. A treatment response to 4-AP with relevance for everyday living was reported by 86% of treated patients. A series of three prospective n-of-1 treatment experiences with on/off design showed marked reduction in daily symptomatic time and symptom severity on 4-AP. Our study characterizes the phenotypic profile, natural history progression, and 4-AP treatment response of GAA-FGF14 ataxia. It paves the way towards large-scale natural history studies and 4-AP treatment trials in this newly discovered, possibly most frequent, and treatable late-onset ataxia.

Achiral 2-pyridone and 4-aminopyridine act as chiral inducers of asymmetric autocatalysis with amplification of enantiomeric excess via the formation of chiral crystals.

Enantiomorphous crystals of achiral 2-pyridone and 4-aminopyridine served as sources of chirality, to induce the asymmetric autocatalysis of 5-pyrimidyl alkanol during the asymmetric addition of diisopropylzinc to the corresponding pyrimidine-5-carbaldehyde, that is, the Soai reaction. Following a significant amplification of enantiomeric excess through asymmetric autocatalysis, highly enantioenriched 5-pyrimidyl alkanol could be synthesized with their corresponding absolute configurations to those of chiral crystals of 2-pyridone and 4-aminopyridine.

Morphological and Functional Alterations in the CA1 Pyramidal Neurons of the Rat Hippocampus in the Chronic Phase of the Lithium-Pilocarpine Model of Epilepsy.

Epilepsy is known to cause alterations in neural networks. However, many details of these changes remain poorly understood. The objective of this study was to investigate changes in the properties of hippocampal CA1 pyramidal neurons and their synaptic inputs in a rat lithium-pilocarpine model of epilepsy. In the chronic phase of the model, we found a marked loss of pyramidal neurons in the CA1 area. However, the membrane properties of the neurons remained essentially unaltered. The results of the electrophysiological and morphological studies indicate that the direct pathway from the entorhinal cortex to CA1 neurons is reinforced in epileptic animals, whereas the inputs to them from CA3 are either unaltered or even diminished. In particular, the dendritic spine density in the str. lacunosum moleculare, where the direct pathway from the entorhinal cortex terminates, was found to be 2.5 times higher in epileptic rats than in control rats. Furthermore, the summation of responses upon stimulation of the temporoammonic pathway was enhanced by approximately twofold in epileptic rats. This enhancement is believed to be a significant contributing factor to the heightened epileptic activity observed in the entorhinal cortex of epileptic rats using an ex vivo 4-aminopyridine model.

Human biodistribution and radiation dosimetry of the demyelination tracer [18F]3F4AP.

PURPOSE: [18F]3F4AP is a novel PET radiotracer that targets voltage-gated potassium (K+) channels and has shown promise for imaging demyelinated lesions in animal models of neurological diseases. This study aimed to evaluate the biodistribution, safety, and radiation dosimetry of [18F]3F4AP in healthy human volunteers. METHODS: Four healthy volunteers (2 females) underwent a 4-h dynamic PET scan from the cranial vertex to mid-thigh using multiple bed positions after administration of 368 ± 17.9 MBq (9.94 ± 0.48 mCi) of [18F]3F4AP. Volumes of interest for relevant organs were manually drawn guided by the CT, and PET images and time-activity curves (TACs) were extracted. Radiation dosimetry was estimated from the integrated TACs using OLINDA software. Safety assessments included measuring vital signs immediately before and after the scan, monitoring for adverse events, and obtaining a comprehensive metabolic panel and electrocardiogram within 30 days before and after the scan. RESULTS: [18F]3F4AP distributed throughout the body with the highest levels of activity in the kidneys, urinary bladder, stomach, liver, spleen, and brain and with low accumulation in muscle and fat. The tracer cleared quickly from circulation and from most organs. The clearance of the tracer was noticeably faster than previously reported in nonhuman primates (NHPs). The average effective dose (ED) across all subjects was 12.1 ± 2.2 µSv/MBq, which is lower than the estimated ED from the NHP studies (21.6 ± 0.6 µSv/MBq) as well as the ED of other fluorine-18 radiotracers such as [18F]FDG (~ 20 µSv/MBq). No differences in ED between males and females were observed. No substantial changes in safety assessments or adverse events were recorded. CONCLUSION: The biodistribution and radiation dosimetry of [18F]3F4AP in humans are reported for the first time. The average total ED across four subjects was lower than most 18F-labeled PET tracers. The tracer and study procedures were well tolerated, and no adverse events occurred.

4-Aminopyridine Protects Nigral Dopaminergic Neurons in the MPTP Mouse Model of Parkinson's Disease.

Various pharmacological blockers targeting K+ channel have been identified to be related to the treatment of Parkinson's disease (PD). Previous studies showed that 4-Aminopyridine (4-AP), a wide-spectrum K+ channel blocker, was able to attenuate apomorphine-induced rotation in parkinsonism rats, indicating the possible beneficial effects in attenuation of PD motor symptoms. However, it is unclear whether 4-AP exhibits neuroprotective effects against the neurodegeneration of substantia nigra (SN)-striatum system in PD. In this study, the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model was employed to evaluate the neuroprotective effects of 4-AP. Results showed that 4-AP inhibited MPTP-induced dopaminergic neuronal loss in the SN as well as dopamine depletion in the striatum. Behavior indexes of open field test and rotarod test confirmed that 4-AP attenuated MPTP-induced motor deficits. We also showed that 4-AP treatment could significantly attenuate the MPTP-induced increase in malonaldehyde (MDA) levels and decrease in superoxide dismutase (SOD) levels. Additionally, MPTP significantly reduced the Bcl-2 expression and promoted the Caspase-3 activation; 4-AP protected dopaminergic neurons against MPTP-induced neurotoxicity by reversing these changes. These results indicate that 4-AP exerts a neuroprotective effect on dopaminergic neurons against MPTP by decreasing oxidative stress and apoptosis. This provides a promising therapeutic target for the treatment of PD.

Design, synthesis and in vitro biological evaluation of 2-aminopyridine derivatives as novel PI3Kδ inhibitors for hematological cancer.

Phosphoinositide-3-kinase (PI3K) involves in regulation of proliferation, cell cycle, and apoptosis, and is overexpressed in most of human malignant tumors. Therefore, the development of PI3K inhibitors has attracted great interest in tumor treatment. In this study, we designed and synthesized a series of 2-aminopyridine derivatives via a bioisosterism strategy. Among them, compound MR3278 showed superior PI3Kδ inhibitory activity (IC50 = 30 nM), as well as higher inhibitory activity to most of AML cells (e.g., MOLM-16 and Mv-4-11 cells with IC50 values of 2.6 µM and 3.7 µM, respectively) than Idelalisib. Further cell studies indicated that MR3278 could induce G2/M phase arrests and cell apoptosis of Mv-4-11 cells via PI3K dependent pathway in a dose dependent manner. In addition, in silico physicochemical and ADMET evaluation revealed its drug-like properties with satisfactory toxicity profiles. These results indicate that MR3278 can be identified as a promising new lead compound to the current PI3Kδ inhibitor and is worthy of further profiling.

Investigating catalytic pathways: a comparative review of homogeneous and heterogeneous catalysis for 3-aroylimidazo[1,2-a]pyridine synthesis.

3-aroylimidazo[1,2-a]pyridines represent a class of derivatives in the imidazo[1,2-a]pyridine family known for their important biological and pharmaceutical activities. Consequently, various methodologies have been designed to simplify the synthesis of this structure, with an emphasis on the use of cost-effective starting materials and environmentally friendly protocols. All the methods developed in recent years (from 2016 to 2023) rely on homogeneous or heterogeneous catalysts. Therefore, we aim to perform a comparative analysis between these two approaches, elucidating their respective advantages and limitations. The first part of this work focuses on techniques employing homogeneous catalysts, followed by the next section devoted to heterogeneous catalysts. This comprehensive review should be of substantial interest to researchers in the fields of organic and medicinal chemistry, as it provides a valuable resource for their research.

Discovery of novel 2-aminopyridine derivatives as ROS1 and ALK dual inhibitors to combat drug-resistant mutants including ROS1G2032R and ALKG1202R.

Clinical treatment by FDA-approved ROS1/ALK inhibitor Crizotinib significantly improved the therapeutic outcomes. However, the emergence of drug resistance, especially driven by acquired mutations, have become an inevitable problem and worsened the clinical effects of Crizotinib. To combat drug resistance, some novel 2-aminopyridine derivatives were designed rationally based on molecular simulation, then synthesised and subjected to biological test. The preferred spiro derivative C01 exhibited remarkable activity against CD74-ROS1G2032R cell with an IC50 value of 42.3 nM, which was about 30-fold more potent than Crizotinib. Moreover, C01 also potently inhibited enzymatic activity against clinically Crizotinib-resistant ALKG1202R, harbouring a 10-fold potency superior to Crizotinib. Furthermore, molecular dynamic disclosed that introducing the spiro group could reduce the steric hindrance with bulky side chain (Arginine) in solvent region of ROS1G2032R, which explained the sensitivity of C01 to drug-resistant mutant. These results indicated a path forward for the generation of anti Crizotinib-resistant ROS1/ALK dual inhibitors.

Effects of 4-Aminopyridine on Combined Nerve and Muscle Injury and Bone Loss.

PURPOSE: Musculoskeletal injuries are common, and peripheral nerve injury (PNI) causes significant muscle and bone loss within weeks. After PNI, 4-aminopyridine (4-AP) improves functional recovery and muscle atrophy. However, it is unknown whether 4-AP has any effect on isolated traumatic muscle injury and PNI-induced bone loss. METHODS: A standardized crush injury was performed on the sciatic nerve and muscles in mice, and the mice were assigned to receive normal saline or 4-AP treatment daily for 21 days. The postinjury motor and sensory function recovery was assessed, injured muscles were processed for histomorphometry, and the tibial bone was scanned for bone density. RESULTS: 4-Aminopyridine significantly accelerated the postinjury motor and sensory function recovery, improved muscle histomorphometry, increased muscle satellite cell numbers, and shifted muscle fiber types after combined nerve and muscle injury. Importantly, the 4-AP treatment significantly reduced PNI-induced bone loss. In contrast, in the case of isolated muscle injury, 4-AP had no effect on functional recovery and bone density, but it improved muscle-specific histomorphometry to a limited extent. CONCLUSIONS: These findings demonstrate the potential beneficial effects of 4-AP on the recovery of muscle morphology and bone density after combined muscle and nerve injury. CLINICAL RELEVANCE: Nerve injuries frequently involve muscle and result in rapid muscle and bone atrophy. In this scenario, 4-AP, in addition to accelerating nerve functional recovery, might work as an adjunctive agent to improve the recovery of injured muscle and attenuate PNI-induced bone loss.

Simple Synthetic Approach to N-(Pyridin-2-yl)imidates from Nitrostyrenes and 2-Aminopyridines via the N-(Pyridin-2-yl)iminonitriles as Intermediates.

A facile, green, synthetic protocol of several substituted N-(pyridin-2-yl)imidates from nitrostyrenes and 2-aminopyridines via the corresponding N-(pyridin-2-yl)iminonitriles as intermediates is reported. The reaction process involved the in situ formation of the corresponding α-iminontriles under heterogeneous Lewis acid catalysis in the presence of Al2O3. Subsequently, α-iminonitriles were selectively transformed into the desired N-(pyridin-2-yl)imidates under ambient conditions and in the presence of Cs2CO3 in alcoholic media. Under these conditions, 1,2- and 1,3-propanediols also led to the corresponding mono-substituted imidates at room temperature. The present synthetic protocol was also developed on one mmol scale, providing access to this important scaffold. A preliminary synthetic application of the present N-(pyridin-2-yl)imidates was carried out for their facile conversion into the N-heterocycles 2-(4-chlorophenyl)-4,5-dihydro-1H-imidazole and 2-(4-chlorophenyl)-1,4,5,6-tetrahydropyrimidine in the presence of the corresponding ethylenediamine and 1,3-diaminopropane.

Metal-Backboned Polymers with Well-Defined Lengths.

Constructing the backbones of polymers with metal atoms is an attractive strategy to develop new functional polymeric materials, but it has yet to be studied due to synthetic challenges. Here, metal atoms are interconnected as the backbones of polymers to yield metal-backboned polymers (MBPs). Rational design of multidentate ligands synthesized via an efficient iterative approach leads to the successful construction of a series of nickel-backboned polymers (NBPs) with well-defined lengths and up to 21 nickel atoms, whose structures are systematically confirmed. These NBPs exhibit strong and length-depended absorption with narrow band gaps, offering promising applications in optoelectronic devices and semiconductors. We also demonstrate the high thermal stability and solution processsability of such nickel-backboned polymers. Our results represent a new opportunity to design and synthesize a variety of new metal-backboned polymers for promising applications in the future.

Modulation of in vitro epileptiform activity by optogenetic stimulation of parvalbumin-positive interneurons.

GABAA signaling is surprisingly involved in the initiation of epileptiform activity since increased interneuron firing, presumably leading to excessive GABA release, often precedes ictal discharges. Field potential theta (4-12 Hz) oscillations, which are thought to mirror the synchronization of interneuron networks, also lead to ictogenesis. However, the exact role of parvalbumin-positive (PV) interneurons in generating theta oscillations linked to epileptiform discharges remains unexplored. We analyzed here the field responses recorded in the CA3, entorhinal cortex (EC), and dentate gyrus (DG) during 8-Hz optogenetic stimulation of PV-positive interneurons in brain slices obtained from PV-ChR2 mice during 4-aminopyridine (4AP) application. This optogenetic protocol triggered similar field oscillations in both control conditions and during 4AP application. However, in the presence of 4AP, optogenetic stimuli also induced: 1) interictal discharges that were associated in all regions with 8-Hz field oscillations and 2) low-voltage fast onset ictal discharges. Interictal and ictal events occurred more frequently during optogenetic activation than during periods of no stimulation. 4AP also increased synchronicity during PV-interneuron activation in all three regions. In opsin-negative mice, optogenetic stimulation did not change the rate of both types of epileptiform activity. Our findings suggest that PV-interneuron recruitment at theta (8 Hz) frequency contributes to epileptiform synchronization in limbic structures in the in vitro 4AP model.NEW & NOTEWORTHY Previous studies have identified contradictory roles of PV-interneurons in ictogenesis and the link between theta oscillations and epileptiform activity remains unexplored. Here, we investigated in vitro the effect of PV-interneuron optogenetic stimulation under 4AP in temporal lobe regions obtained from PV-ChR2 transgenic mice. Under theta (8 Hz) optogenetic stimulation and 4AP application, interictal spikes and low-voltage fast onset ictal discharges were triggered, suggesting that the activation of PV-interneurons favors synchronization and ictogenesis.

Aging-associated susceptibility to stress-induced ventricular arrhythmogenesis is attenuated by tetrodotoxin.

Aging is associated with increased prevalence of life-threatening ventricular arrhythmias, but mechanisms underlying higher susceptibility to arrhythmogenesis and means to prevent such arrhythmias under stress are not fully defined. We aimed to define differences in aging-associated susceptibility to ventricular fibrillation (VF) induction between young and aged hearts. VF induction was attempted in isolated perfused hearts of young (6-month) and aged (24-month-old) male Fischer-344 rats by rapid pacing before and following isoproterenol (1 µM) or global ischemia and reperfusion (I/R) injury with or without pretreatment with low-dose tetrodotoxin, a late sodium current blocker. At baseline, VF could not be induced; however, the susceptibility to inducible VF after isoproterenol and spontaneous VF following I/R was 6-fold and 3-fold higher, respectively, in old hearts (P < 0.05). Old animals had longer epicardial monophasic action potential at 90% repolarization (APD90; P < 0.05) and displayed a loss of isoproterenol-induced shortening of APD90 present in the young. In isolated ventricular cardiomyocytes from older but not younger animals, 4-aminopyridine prolonged APD and induced early afterdepolarizations (EADs) and triggered activity with isoproterenol. Low-dose tetrodotoxin (0.5 µM) significantly shortened APD without altering action potential upstroke and prevented 4-aminopyridine-mediated APD prolongation, EADs, and triggered activity. Tetrodotoxin pretreatment prevented VF induction by pacing in isoproterenol-challenged hearts. Vulnerability to VF following I/R or catecholamine challenge is significantly increased in old hearts that display reduced repolarization reserve and increased propensity to EADs, triggered activity, and ventricular arrhythmogenesis that can be suppressed by low-dose tetrodotoxin, suggesting a role of slow sodium current in promoting arrhythmogenesis with aging.

Functions of potassium channels blocked by low micromolar 4-aminopyridine in the crayfish nervous system.

4-aminopyridine (4-AP) is a potassium channel blocker that has been used to treat patients with multiple sclerosis and Lambert-Eaton disease. The concentration of this drug in the blood of patients was estimated to be in low or submicromolar range. Animal studies have shown that 4-AP at such low concentration selectively blocks a subset of channels in Kv1 or Kv3 families. The crayfish opener neuromuscular junction and ventral superficial flexor (VSF) preparations were used to examine functions of K+ channels blocked by low concentrations of 4-AP. At opener motor axons, intracellular recordings show that 4-AP could increase action potential (AP) amplitude, duration, and after-depolarization (ADP) at 10 µM. As 4-AP concentration was increased, in twofold steps, AP amplitude did not increase further up to 5 mM. AP duration and ADP increased significantly mainly in two concentration ranges, 10-50 µM and 1-5 mM. The effects of 50 µM 4-AP on the VSF were less consistent than that observed at the opener motor axons. 4-AP did not change AP amplitude of motor axons recorded with an extracellular electrode and change in AP repolarizing potential was observed in ∼25% of the axons. EPSP recorded simultaneously with AP showed an increase in amplitude with 4-AP treatment only in 30% of the axon-EPSP pairs. 4-AP also increased firing frequencies of ∼50% of axons. In four animals, 4-AP "awakened" the firing of APs from an axon that was silent before the drug. The mixture of positive and negative 4-AP effects summarized above was observed in the same VSF preparations in all cases (n = 8). We propose that there is a significant diversity in the density 4-AP-sensitive potassium channels among motor axons of the VSF. Functional significance in the differences of 4-AP sensitivity of the two motor systems is discussed.

In silico and in vivo neuropharmacological evaluation of two γ-amino acid isomers derived from 2,3-disubstituted benzofurans, as ligands of GluN1-GluN2A NMDA receptor.

The GABAergic and glutamatergic neurotransmission systems are involved in seizures and other disorders of the central nervous system (CNS). Benzofuran derivatives often serve as the core in drugs used to treat such neurological disorders. The aim of this study was to synthesize new γ-amino acids structurally related to GABA and derived from 2,3-disubstituted benzofurans, analyze in silico their potential toxicity, ADME properties, and affinity for the GluN1-GluN2A NMDA receptor, and evaluate their potential activity and neuronal mechanisms in a murine model of pentylenetetrazol (PTZ)- and 4-aminopyridine (4-AP)-induced seizures. The in silico analysis evidenced a low risk of toxicity for the test compounds as well as the probability that they can cross the blood-brain barrier (BBB) to reach their targets in the CNS. According to docking simulations, these compounds bind at the active site of the NMDA glutamate receptor with high affinity. The in vivo assays demonstrated that 4 protects against 4-AP-induced seizure episodes, suggesting negative allosteric modulation (NAMs) at the glutamatergic NMDA receptor. Contrarily, 3 (the regioisomer of 4) and its racemic derivatives (cis-2,3-dihydrobenzofurans) were previously described to exacerbate such episodes, pointing to their positive allosteric modulation (PAMs) of the same receptor.

Concentration-QT modelling of the novel DHFR inhibitor P218 in healthy male volunteers.

AIMS: Given the increasing emergence of drug resistance in Plasmodium, new antimalarials are urgently required. P218 is an aminopyridine that inhibits dihydrofolate reductase being developed as a malaria chemoprotective drug. Assessing the effect of new compounds on cardiac intervals is key during early drug development to determine their cardiac safety. METHODS: This double-blind, randomized, placebo-controlled, parallel group study evaluated the effect of P218 on electrocardiographic parameters following oral administration of seven single-ascending doses up to 1000 mg in 56 healthy volunteers. Participants were randomized to treatment or placebo at a 3:1 ratio. P218 was administered in the fasted state with standardized lunch served 4 hours after dosing. 12-lead ECGs were recorded in triplicate at regular intervals on the test day, and at 48, 72, 120, 168, 192 and 240 hours thereafter. Blood samples for pharmacokinetic evaluations were collected at similar time points. Concentration-effect modelling was used to assess the effect of P218 and its metabolites on cardiac intervals. RESULTS: Concentration-effect analysis showed that P218 does not prolong the QTcF, J-Tpeak or TpTe interval at all doses tested. No significant changes in QRS or PR intervals were observed. Two-sided 90% confidence intervals of subinterval effects of P218 and its metabolites were consistently below the regulatory concern threshold for all doses. Study sensitivity was confirmed by significant shortening of QTcF after a meal. CONCLUSION: Oral administration of P218 up to 1000 mg does not prolong QTcF and does not significantly change QRS or PR intervals, suggesting low risk for drug-induced proarrhythmia.

The role of potassium channels in the proliferation and migration of endometrial adenocarcinoma HEC1-A cells.

BACKGROUND: Endometrial cancer is the most common gynecological cancer in developed countries. Potassium channels, which have many types, are suggested to play a major role in cancer progression. However, their role in endometrial cancer has not been fully investigated. We aimed to demonstrate whether the ATP-sensitive potassium channel blocker glibenclamide, voltage-sensitive potassium channel blocker 4-aminopyridine, non-selective (voltage-sensitive and calcium-activated) potassium channels blocker tetraethylammonium and potassium chloride (KCl) have any effect on the proliferation and migration of HEC1-A cells. METHODS AND RESULTS: Proliferation and migration were evaluated by real-time cell analysis (xCELLigence system) and wound healing assays, respectively. Proliferation was reduced by glibenclamide (0.1 and 0.2 mM, P < 0.05 and P < 0.01, respectively), 4-aminopyridine (10 and 20 mM, P < 0.001) and tetraethylammonium (10 and 20 mM, P < 0.01 and P < 0.001, respectively). However, KCl did not change the proliferation. Migration was reduced by glibenclamide (0.01, 0.1 and 0.2 mM, P < 0.001, P < 0.001 and P < 0.01, respectively) and 4-aminopyridine (10 and 20 mM, P < 0.05 and P < 0.01, respectively). Tetraethylammonium did not change migration. However, KCl reduced it (10, 25 and 50 mM, P < 0.05, P < 0.01 and P < 0.01, respectively). Both proliferation and migration were reduced by glibenclamide and 4-aminopyridine. However, tetraethylammonium only reduced proliferation and KCl only reduced migration. CONCLUSIONS: Potassium channels have an important role in HEC1-A cell proliferation and migration and potassium channel blockers needs to be further investigated for their therapeutic effect in endometrial cancer.

Design, synthesis and biological evaluation of 2-aminopyridine derivatives as USP7 inhibitors.

A series of novel 2-aminopyridine derivatives 1-26 have been designed and synthesized by structural modifications on a lead USP7 inhibitor, GNE6640. All the compounds were evaluated for their USP7 inhibitory activities. The results showed that most of the compounds have good USP7 inhibitory activities at the concentration of 50 µM. Among them, compounds 7, 14 and 21 are the most potential ones from each category with the IC50 values of 7.6 ± 0.1 µM, 17.0 ± 0.2 µM and 11.6 ± 0.5 µM, respectively. Compounds 7 and 21 expressed significant binding interactions with USP7 by surface plasmon resonance (SPR)-based binding assay, but both of them presented moderate antiproliferative activities against HCT116 cells. They could effectively promote MDM2 degradation, p53 stabilization and p21 gene expression in the western blot analysis.

The efficacy of combining topiramate and 4-aminopyridine to reduce relapses and interictal progression in two cases of episodic ataxia type 2.

BACKGROUND: Episodic ataxia type 2 is an autosomal dominant channelopathy, caused by genetic variants in the voltage-dependent calcium channel a-1 subunit (CACNA1A), which is characterized by intermittent episodes of vertigo and ataxia. A slow progression of cerebellar signs is commonly observed in the course of the disease. Treatment with the carbonic anhydrase inhibitor acetazolamide is recommended. METHODS: We report the cases of two patients with EA-2 and migraine, linked to a novel CACNA1A mutation associated with disabling ictal and interictal disease, which did not respond to acetazolamide. RESULTS: A 30-year-old woman and a 50-year-old man, who was a ski instructor, reported disabling episodes of rotatory vertigo and progressive interictal ataxia. In both cases, the disease progressed despite treatment with acetazolamide. The concomitant use of topiramate and 4-aminopyridine significantly reduced the frequency and severity of relapses and migraine and improved the interictal cerebellar progression in both cases. CONCLUSIONS: We propose combined applications of topiramate and 4-aminopyridine in refractory cases and those with poor tolerance to acetazolamide and also in those with frequent associated migraine. The effectiveness of this combination of drugs for treating intermittent ataxic episodes and interictal signs in EA-2 has not been previously reported.