Disease relevance of 4-aminopyridine

• These data indicate that NMDA-mediated ictal discharges induced by 4AP originate in the entorhinal cortex; such a conclusion is in line with clinical evidence obtained in temporal lobe epilepsy patients [1].
• We conclude that at least some patients with acquired neuromyotonia have antibodies directed against aminopyridine- or alpha-dendrotoxin-sensitive K+ channels in motor and sensory neurons, and they are likely to be implicated in the disease process [2].
• A crossover comparison of the two agents suggested that AP produces more central nervous system side effects (dizziness and confusion), whereas DAP produces more peripheral side effects (paresthesias and abdominal pain) [3].
• OBJECTIVE: To evaluate the efficacy of 4-aminopyridine sustained release (4AP SR) (fampridine, EL-970) using quantitative measures of motor function in multiple sclerosis (MS) patients [4].
• Through a combination of iterative medicinal chemistry and X-ray crystal structure based design, one of these leads was developed into the novel aminopyridine derivative 9, a low micromolar inhibitor of FabI from S. aureus (IC(50) = 2.4 microM) and Haemophilus influenzae (IC(50) = 4.2 microM) [5].

Psychiatry related information on 4-aminopyridine

• Tetrahydroaminoacridine, an aminopyridine analog with anticholinesterase properties, produces clinical improvement in behavioral deficits due to Alzheimer's disease [6].

High impact information on 4-aminopyridine

• In hippocampal neurons, a slowly inactivating aminopyridine-sensitive transient potassium current, D-current, influences the time course of action potential repolarization and therefore activity-dependent Ca2+ entry [7].
• Preliminary studies of AP demonstrated benefit in many temperature-sensitive patients with MS, and improvement of function was found in a large randomized double-blind, placebo-controlled crossover trial of 3 months of oral treatment in 68 patients with MS [3].
• An aminopyridine dimer serves as a model for Watson-Crick base pairs, where similar reactions have been predicted by theory [8].
• Aminopyridine block of Kv1.1 potassium channels expressed in mammalian cells and Xenopus oocytes [9].
• Rather, the data are consistent with a simple binding scheme incorporating no changes in gating kinetics which conceives of aminopyridine molecules binding to closed K channels and being released from open channels in a voltage-dependent manner [10].

Chemical compound and disease context of 4-aminopyridine

• Uridine release during aminopyridine-induced epilepsy [11].
• Nitric oxide synthase inhibitor facilitates focal seizures induced by aminopyridine in rat [12].
• The use of 4-aminopyridine (fampridine) in demyelinating disorders [13].

Biological context of 4-aminopyridine

• Each compound occupies the same region of the active site and projects an aminopyridine, a central hydrophobic group, and an aryl group, into the S1, S2, and aryl subsites on thrombin [14].
• The benzoxazole 49, a cyclic analogue of 16, was a very potent enhancer of insulin sensitivity, and by modification of the aromatic heterocycle, an aminopyridine, 37, was identified as a lead compound from SAR studies [15].
• A transient, low-threshold K+ current, which was 4AP sensitive and showed significant steady-state inactivation in the physiological membrane potential range (-40 to -60 mV), was evoked from a holding potential of -100 mV [16].
• Large potassium signals and slow potentials evoked during aminopyridine or barium superfusion in cat cerebellum [17].
• Studies of 7 beta-[2-(aminoaryl)acetamido]-cephalosporin derivatives. I. Synthesis and structure-activity relationships in the aminopyridine series [18].

Anatomical context of 4-aminopyridine

• 1 4-Aminopyridine methiodide (4-APMI), a quaternary analogue of aminopyridine (4-AP), was tested for neuromuscular facilitatory actions on the chick biventer cervicis and frog sartorius nerve-muscle preparations [19].
• Our findings indicate that action potentials of variable amplitude recorded from CA3 pyramidal cells in the 4AP model are generated at or near the terminal region of the Schaffer collaterals and that they represent TTX-sensitive ectopic events [20].
• Removal of the endothelium, application of 4-aminopyridine (4-AP, an inhibitor of aminopyridine sensitive K+ channels), or use of glibenclamide (an inhibitor of ATP-sensitive K+ channels) did not affect the vasodilator response to fluoxetine [21].
• Aminopyridine-sensitivity of spinal cord white matter studied in vitro [22].
• Properties of depolarizing plateau potentials in aminopyridine-induced ictal seizure foci of cat motor cortex [23].

Associations of 4-aminopyridine with other chemical compounds

• PURPOSE: We determined how CA3-driven interictal discharges block ictal activity generated in the entorhinal cortex during bath application of 4-aminopyridine (4AP, 50 microM) [24].
• RESULTS: 4AP induced N-methyl-d-aspartate (NMDA) receptor-dependent ictal discharges that originated in the entorhinal cortex, disappeared over time, but were reestablished by cutting the Schaffer collateral (n = 20) or by depressing CA3 network excitability with local application of glutamatergic receptor antagonists (n = 5) [24].
• Electrical stimulation (Schaffer collaterals and stratum oriens) combined with different aminopyridine compounds (AP) were used for neuronal activation [25].
• It was also resistant to inactivation with periodate-oxidized aminopyridine adenine dinucleotide phosphate, an affinity label for malic enzyme [26].
• N,N'-Dimethyl-N,N'-bis[(4-amidylphenyl)aminocarbonyl]-2,6-di aminopyridine (1) and 1,3-bis[5-(glycylamino)pyrid-2-yl]urea (3) showed remarkable DNA-binding abilities as determined by ultrafiltration assay using calf thymus DNA, their potencies being equal to and half that of netropsin, respectively [27].

Gene context of 4-aminopyridine

• Furthermore, the fact that alpha 2-receptors and adenosine A1 receptor agonists can influence the release of NA evoked by 4-AP suggests that these drugs may have actions that are independent of blockade of aminopyridine-sensitive K(+)-channels [28].
• The structure-activity relationships of 5,6-positions of aminopyridine carboxamide-based c-Jun N-terminal Kinase (JNK) inhibitors were explored to expand interaction with the kinase specificity and ribose-binding pockets [29].
• Structural modifications of the aminopyridine P(1)(') group of imidazole acetic acid based TAFIa inhibitors led to the discovery of the aminocyclopentyl analog 28, a 1 nM TAFIa inhibitor with CLT(50) functional activity of 14 nM but without selectivity against CPB [30].

Analytical, diagnostic and therapeutic context of 4-aminopyridine

• Electrical stimulation combined with application of aminopyridine compounds led to electron dense deposits of 60-400 nm diameter, mainly restricted to the activated input layers [25].
• An aminopyridine-sensitive, early outward current recorded in vivo in neurons of the precruciate cortex of cats using single-electrode voltage-clamp techniques [31].
• Plasma concentration profiles of the K+ channel-blocking compound Fampridine were obtained from (1) control subjects (n = 6) following oral administration of doses of 10, 15, 20, and 25 mg and (2) patients with spinal cord injury (SCI) (n = 11) following a single oral dose of 10 mg of an immediate-release formulation [32].
• Elan has used its Intestinal Protective Drug Absorption System (IPDAS) drug delivery system to produce Neurelan, which is a controlled-release (twice daily) formulation of fampridine [223736] [33].

References