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Sci Rep
2020 Jan 09;101:52. doi: 10.1038/s41598-019-56245-w.
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Structure-activity relationship studies of four novel 4-aminopyridine K+ channel blockers.
Rodríguez-Rangel S
,
Bravin AD
,
Ramos-Torres KM
,
Brugarolas P
,
Sánchez-Rodríguez JE
.
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4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (KV1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [18F]3F4AP, a radiofluorinated analog of 4AP, also binds to KV1 channels and can be used as a PET tracer for the detection of demyelinated lesions in rodent models of MS. Here, we investigate four novel 4AP derivatives containing methyl (-CH3), methoxy (-OCH3) as well as trifluoromethyl (-CF3) in the 2 and 3 position as potential candidates for PET imaging and/or therapy. We characterized the physicochemical properties of these compounds (basicity and lipophilicity) and analyzed their ability to block Shaker K+ channel under different voltage and pH conditions. Our results demonstrate that three of the four derivatives are able to block voltage-gated potassium channels. Specifically, 3-methyl-4-aminopyridine (3Me4AP) was found to be approximately 7-fold more potent than 4AP and 3F4AP; 3-methoxy- and 3-trifluoromethyl-4-aminopyridine (3MeO4AP and 3CF34AP) were found to be about 3- to 4-fold less potent than 4AP; and 2-trifluoromethyl-4-AP (2CF34AP) was found to be about 60-fold less active. These results suggest that these novel derivatives are potential candidates for therapy and imaging.
Armstrong,
A model for 4-aminopyridine action on K channels: similarities to tetraethylammonium ion action.
2001, Pubmed
Armstrong,
A model for 4-aminopyridine action on K channels: similarities to tetraethylammonium ion action.
2001,
Pubmed
Arroyo,
Acute demyelination disrupts the molecular organization of peripheral nervous system nodes.
2004,
Pubmed
Basuli,
An efficient new method for the synthesis of 3-[18 F]fluoro-4-aminopyridine via Yamada-Curtius rearrangement.
2018,
Pubmed
Berger,
Effects of new 4-aminopyridine derivatives on neuromuscular transmission and on smooth muscle contractility.
1989,
Pubmed
Bostock,
The effects of 4-aminopyridine and tetraethylammonium ions on normal and demyelinated mammalian nerve fibres.
1981,
Pubmed
Brugarolas,
Detecting Demyelination by PET: The Lesion as Imaging Target.
2018,
Pubmed
Brugarolas,
Synthesis of meta-substituted [(18)F]3-fluoro-4-aminopyridine via direct radiofluorination of pyridine N-oxides.
2016,
Pubmed
Brugarolas,
Automated Radiochemical Synthesis of [18F]3F4AP: A Novel PET Tracer for Imaging Demyelinating Diseases.
2017,
Pubmed
Brugarolas,
Development of a PET radioligand for potassium channels to image CNS demyelination.
2018,
Pubmed
Caballero,
Molecular docking study of the binding of aminopyridines within the K+ channel.
2007,
Pubmed
Choquet,
Mechanism of 4-aminopyridine action on voltage-gated potassium channels in lymphocytes.
1992,
Pubmed
Coman,
Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis.
2006,
Pubmed
Davis,
Orally administered 4-aminopyridine improves clinical signs in multiple sclerosis.
1990,
Pubmed
Devaux,
Effects of K+ channel blockers on developing rat myelinated CNS axons: identification of four types of K+ channels.
2002,
Pubmed
Eng,
Development of 4-AP and TEA sensitivities in mammalian myelinated nerve fibers.
1988,
Pubmed
Fehlings,
Changes in pharmacological sensitivity of the spinal cord to potassium channel blockers following acute spinal cord injury.
1996,
Pubmed
Goodman,
Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial.
2009,
Pubmed
Gutman,
International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels.
2005,
Pubmed
Hayes,
Preclinical trial of 4-aminopyridine in patients with chronic spinal cord injury.
1993,
Pubmed
Hermann,
Effects of 4-aminopyridine on potassium currents in a molluscan neuron.
1981,
Pubmed
Hoshi,
Biophysical and molecular mechanisms of Shaker potassium channel inactivation.
1990,
Pubmed
,
Xenbase
Howe,
On the active form of 4-aminopyridine: block of K+ currents in rabbit Schwann cells.
1991,
Pubmed
Iaci,
Dalfampridine improves sensorimotor function in rats with chronic deficits after middle cerebral artery occlusion.
2013,
Pubmed
Jensen,
Changes in cognition, arm function and lower body function after slow-release Fampridine treatment.
2014,
Pubmed
Jones,
Effects of 4-aminopyridine in patients with multiple sclerosis.
1983,
Pubmed
Jukkola,
K+ channel alterations in the progression of experimental autoimmune encephalomyelitis.
2012,
Pubmed
Karimi-Abdolrezaee,
Temporal and spatial patterns of Kv1.1 and Kv1.2 protein and gene expression in spinal cord white matter after acute and chronic spinal cord injury in rats: implications for axonal pathophysiology after neurotrauma.
2004,
Pubmed
Kirsch,
Segmental exchanges define 4-aminopyridine binding and the inner mouth of K+ pores.
1993,
Pubmed
Kirsch,
Site of action and active form of aminopyridines in squid axon membranes.
1983,
Pubmed
Kirsch,
3,4-diaminopyridine. A potent new potassium channel blocker.
1978,
Pubmed
Kocsis,
Aminopyridine-sensitivity of spinal cord white matter studied in vitro.
1985,
Pubmed
Leung,
Potassium channel blocker, 4-aminopyridine-3-methanol, restores axonal conduction in spinal cord of an animal model of multiple sclerosis.
2011,
Pubmed
Lewis,
Predictors of Response to 4-Aminopyridine in Chronic Canine Spinal Cord Injury.
2019,
Pubmed
Maddison,
Treatment for Lambert-Eaton myasthenic syndrome.
2003,
Pubmed
McCormack,
A characterization of the activating structural rearrangements in voltage-dependent Shaker K+ channels.
1994,
Pubmed
Rasband,
Potassium channel distribution, clustering, and function in remyelinating rat axons.
1998,
Pubmed
Ritchie,
Sodium and potassium channels in demyelinated and remyelinated mammalian nerve.
1981,
Pubmed
Sherratt,
Effects of 4-aminopyridine on normal and demyelinated mammalian nerve fibres.
1980,
Pubmed
Sinha,
Functional changes in genetically dysmyelinated spinal cord axons of shiverer mice: role of juxtaparanodal Kv1 family K+ channels.
2006,
Pubmed
Stefani,
Cut-open oocyte voltage-clamp technique.
1998,
Pubmed
,
Xenbase
Stefoski,
4-Aminopyridine improves clinical signs in multiple sclerosis.
1987,
Pubmed
Sun,
Novel potassium channel blocker, 4-AP-3-MeOH, inhibits fast potassium channels and restores axonal conduction in injured guinea pig spinal cord white matter.
2010,
Pubmed
Trimmer,
Localization of voltage-gated ion channels in mammalian brain.
2004,
Pubmed
Vacher,
Localization and targeting of voltage-dependent ion channels in mammalian central neurons.
2008,
Pubmed
Wang,
Hypomyelination alters K+ channel expression in mouse mutants shiverer and Trembler.
1995,
Pubmed
Waxman,
Molecular dissection of the myelinated axon.
1993,
Pubmed
Woodhull,
Ionic blockage of sodium channels in nerve.
1973,
Pubmed
Yeh,
Interactions of aminopyridines with potassium channels of squid axon membranes.
1976,
Pubmed
