A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction

Abstract

K channels containing Kv1.1 α subunits, which become prevalent at internodes in demyelinated axons, may underlie their dysfunctional conduction akin to muscle weakness in multiple sclerosis. Small inhibitors were sought with selectivity for the culpable hyper-polarizing K currents. Modeling of interactions with the extracellular pore in a Kv1.1-deduced structure identified diaryldi(2-pyrrolyl)methane as a suitable scaffold with optimized alkyl ammonium side chains. The resultant synthesized candidate [2,2'-((5,5'(di-p-topyldiaryldi(2-pyrrolyl)methane)bis(2,2'carbonyl)bis(azanediyl)) diethaneamine·2HCl] (8) selectively blocked Kv1.1 channels (IC ≈ 15 μM) recombinantly expressed in mammalian cells, induced a positive shift in the voltage dependency of K current activation, and slowed its kinetics. It preferentially inhibited channels containing two or more Kv1.1 subunits regardless of their positioning in concatenated tetramers. In slices of corpus callosum from mice subjected to a demyelination protocol, this novel inhibitor improved neuronal conduction, highlighting its potential for alleviating symptoms in multiple sclerosis.

Synthesis of model southern rim structures of photosynthetic tetrapyrroles and phyllobilins

“…50 Typical derivatization includes formation of the benzylester, 51 amide, 52 and carboxylic acid 53 moieties. Here, the Nazarov product 6-HH was treated with trichloroacetic anhydride 54 to give the trichloroacetyl product 7 , which was isolated by simple filtration in 71% yield (Scheme 6, top). The trichloroacetylation occurs selectively at the α-position of the unsubstituted pyrrole rather than the α-position of the annulated pyrrole, as the latter is deactivated by the β-keto substituent.…”

“…Following a reported procedure, 54 a solution of 6-HH (25.0 mg, 0.102 mmol) and DMAP (3.1 mg, 0.020 mmol) in anhydrous CH 2 Cl 2 (1 mL) at 0 °C was treated dropwise with 2,2,2-trichloroacetic anhydride (22.5 μL, 0.123 mmol). The resulting solution under argon was allowed to warm to room temperature and stirred over the course of 2 h. Then, the reaction mixture was diluted with CH 2 Cl 2 and filtered to obtain a white solid (25.0 mg, 71%): decomposition observed at 220 °C; 1 H NMR (CD 3 OD, 600 MHz) δ 7.33 (d, J = 4.2 Hz, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.32 (d, J = 3.0 Hz, 1H), 6.07 (d, J = 3.6 Hz, 1H), 4.97–4.98 (d, J = 3.0 Hz, 1H), 3.95–3.96 (d, J = 3.0 Hz, 1H), 3.80 (s, 3H); 13 C{ 1 H} NMR (CD 3 OD, 150 MHz) δ 190.5, 173.7, 170.8, 159.7, 142.0, 128.9, 126.4, 124.0, 123.2, 110.1, 103.5, 68.3, 53.1, 49.6, 38.7; HRMS (ESI-TOF) m / z : [M + H] + calcd for C 15 H 11 Cl 3 N 2 O 4 , 388.98572; found, 388.98558; λ abs (MeOH) 321 nm.…”

AgTx2-GFP, Fluorescent Blocker Targeting Pharmacologically Important Kv1.x (x = 1, 3, 6) Channels

“…Inherited loss-of-function mutations of the K v 1.1 channel in humans are associated with episodic ataxia type I [ 61 ], while some other deletions or mutations of the K v 1.1 and K v 1.2 channels provoke epilepsy [ 62 ]. Although the blockage of K v 1.1 and K v 1.2 channels has no therapeutic value in cases of increased excitability of neurons, the inhibition of K v 1.1 channels in inhibitory (demyelinated) axons is known to improve neuronal conduction in multiple sclerosis [ 63 ]. While the physiological role of the K v 1.6 channel, which is widely expressed in the central nervous system and peripheral neurons, is still poorly determined, the localization of K v 1.6 in microglial cells in the striatum suggests its potential role in neuroinflammation and striatal disorders, such as Parkinson’s disease [ 64 ].…”

Kv1.1 Channelopathies: Pathophysiological Mechanisms and Therapeutic Approaches

“…As mentioned above, some negative modulators of Kv1.1 channels exist. Kv1.1 and Kv1.2 channels co-localize at the juxtaparanodal region of axons throughout the nervous system and their mislocalization appears to contribute to impaired neural transmission and muscle weakness secondary to the demyelination process in multiple sclerosis [131]. So far, fampridine, a modified release form of the Kv channel blocker 4-aminopyridine, represents the first and only medication to improve the ability to walk for those suffering from multiple sclerosis [131].…”

“…Kv1.1 and Kv1.2 channels co-localize at the juxtaparanodal region of axons throughout the nervous system and their mislocalization appears to contribute to impaired neural transmission and muscle weakness secondary to the demyelination process in multiple sclerosis [131]. So far, fampridine, a modified release form of the Kv channel blocker 4-aminopyridine, represents the first and only medication to improve the ability to walk for those suffering from multiple sclerosis [131]. For this reason, the negative modulation of Kv1.1 and kv1.2 channels are subject to drug discovery program and some selective blockers have been developed in the perspective to find more specific and safer medications for this disease [113,132].…”