Multiple Sclerosis and Related Conditions
John W. Scadding, Nicholas A. Losseff in Clinical Neurology, 2011
The aminopyridines (4-aminopyridine (4-AP) and 3,4-diaminopyridine (3–4 DAP)) inhibit potassium channels and widen the nerve action potential, reversing conduction block in experimentally demyelinated axons. These agents act similarly on synaptic potassium channels. Their ability to reverse conduction block in fibres with a critically low safety factor has led to clinical studies in patients with MS, particularly those with severe and progressive disability in whom the symptoms show temperature dependence. 4-AP crosses the blood–brain barrier more easily, and has therefore been studied more intensively than 3–4 DAP. Both agents have a small but significant beneficial effect on disability, but their widespread use has been limited by a narrow therapeutic index. They are associated with significant side effects, including dizziness, paraesthesiae and abdominal pain. At higher doses, they may precipitate an encephalopathy or seizures. 4-AP is currently available for unlicensed treatment of highly selected patients. The drug is introduced at a low dose of 5 mg given once or twice daily, and dosage increments must be titrated carefully to a maximum dose of 10 mg taken three times daily. These practical difficulties with the use of potassium channel blockers have led to work using a slow release formulation of 4-AP, fampridine, and a recent trial suggested that the drug could be used relatively safely and that it was capable of improving gait in a subset of ambulant patients with established disability.
Neurobiology of the Gustatory Zone of Nucleus Tractus Solitarius
I. Robin A. Barraco in Nucleus of the Solitary Tract, 2019
These complex firing patterns are mediated by different ionic conductances. Ionic channel blockers have now been used to characterize the conductances involved in the intrinsic firing properties of rNTS neurons.19 Application of 4-aminopyridine, used to block K channels, results in reduction or elimination of the delay in firing of Group II neurons. Voltage-clamp recordings of Group II neurons reveal that the firing delay is due to a transient outward K+ current partially inactivated around the resting membrane potential and blocked by 4-aminopyridine (Figure 3). Hyperpolarization removes this inactivation causing a delay in the firing of the neuron. Based on its pharmacology and voltage dependence, this current is similar to the A-current (IKA) previously described in many other CNS neurons including the caudal NTS.20-23
Medical Countermeasures for Intoxication by Botulinum Neurotoxin
Brian J. Lukey, James A. Romano, Salem Harry in Chemical Warfare Agents, 2019
The inability of 3,4-DAP infusion to produce complete reversal of BoNT/A-mediated paralysis in the infusion studies may have resulted from the dose being too low. Higher doses could not be examined because the dose used was at the limit of aqueous solubility, indicating a need for a more potent K+ channel blocker. To achieve this aim, a series of aminopyridines, from both commercial and custom sources, were tested in the mouse phrenic nerve–hemidiaphragm assay by Adler and Borrell (unpublished observations). Table 14.1 shows a sample of the compounds tested and the percentage potentiation of twitch tension achieved. Test compounds were added at 100 µM after tensions were depressed to ~20% of control by exposure to 2 pM BoNT/A. Most compounds were weak or inactive in this assay, as exemplified by 6-aminopyridine-3-carboxylic acid. The remaining compounds, including those with single amine groups (2-aminopyridine [2-AP], 3-aminopyridine [3-AP], 4-aminopyridine [4-AP]) or two amine groups (2,3-diaminopyridine [2,3-DAP]), were all found to be less potent than 3,4-DAP. These results agree with those of Molgó et al. (1985) and indicate the difficulty of discovering aminopyridine analogs more potent than 3,4-DAP for blocking K+ channels at motor nerve terminals.
Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities
Published in Expert Opinion on Investigational Drugs, 2021
Laurent Servais, Giovanni Baranello, Mariacristina Scoto, Aurore Daron, Maryam Oskoui
Amifampridine (marketed as Firdapse) is currently approved for the treatment of Lambert-Eaton myasthenic syndrome, an autoimmune disorder in which antibodies target voltage-gated Ca2+ channels, resulting in a pre-synaptic pathology of NMJs. Amifampridine acts by blocking pre-synaptic K+ channels thus increasing duration of acetylcholine release in the NMJ cleft [50]. Amifampridine has also been successfully used to treat the post-synaptic NMJ disorder muscle-specific kinase myasthenia gravis and thus appears to be effective in treating both pre- and post-synaptic defects. NMJ defects are a key component in the SMA pathology, as demonstrated both in preclinical and in clinical studies [51–53]. A phase 2 randomized cross-over study to evaluate the safety, tolerability, and efficacy of amifampridine in ambulatory SMA3 patients is currently ongoing (NCT03781479). A cross-over study in adult ambulant SMA3 patients using a similar compound, an extended-release formulation of 4-aminopyridine, that blocks voltage-sensitive potassium channels in the central and peripheral nervous system is now completed and results are pending (NCT01645787).
Leucine-rich repeat kinase 2 inhibitors: a patent review (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2020
As a typical kinase scaffold, aminopyridine analogues as LRRK2 inhibitors have been extensively investigated as reported in numerous research articles and patents. The early generations of this chemo-type (Figure 7) such as CZC-54,252 (21) reported by Cellzome [48], LRRK2-IN-1 (22) and TAE684 (23) reported by the Gray group [49,50] have been widely used as tool compounds to explore the biological function and mechanism of LRRK2. On the other hand, the lack of selectivity, CNS penetration and/or high plasma protein binding limited the potential of aminopyridine analogues for murine PD models and clinical uses. Extensive efforts on the optimization of selectivity and physicochemical properties of the series led to the discovery of several promising aminopyridine LRRK2 inhibitors including GNE7915 (1) and GNE-9605 (2) by Genentech [30,31].
Current challenges in the pathophysiology, diagnosis, and treatment of paroxysmal movement disorders
Published in Expert Review of Neurotherapeutics, 2021
Cécile Delorme, Camille Giron, David Bendetowicz, Aurélie Méneret, Louise-Laure Mariani, Emmanuel Roze
CACNA1A-related episodic ataxia usually starts in childhood or adolescence [148]. It is typically characterized by attacks of cerebellar ataxia (a few episodes per year to several episodes per week), often associated with nausea and vertigo, lasting from a few hours to a few days. Precipitating factors may include alcohol or coffee intake, stress, and exercise. Patients tend to develop slowly progressive ataxia with nystagmus over the course of the disease. Additional manifestations of the disease may include migraine, epilepsy, dystonia, fluctuating weakness, and intellectual disability. The majority of patients have a good response to acetazolamide [148]. Treatment with 4-aminopyridine could be an interesting alternative [149].
Related Knowledge Centers
- 2-Aminopyridine
- 3-Aminopyridine
- 4-Aminopyridine