Disease relevance of Chromanol

• Selective blockers (chromanol 293B, HMR-1556, L-735,821) of the KvLQT1 plus minK channel, which carriy the slow delayed rectifier potassium current (I(Ks)), were also considered to treat arrhythmias, including atrial fibrillation (AF) [1].
• Several of the new chromanol compounds have high affinity for the racemic [3H]CP-101,606 binding site on the NMDA receptor and protect against glutamate toxicity in cultured hippocampal neurons [2].
• A novel phospholipid containing a chromanol structure at its polar head group was synthesized from egg yolk phosphatidylcholine and 2,5,7,8-tetramethyl-6-hydroxy-2-(hydroxyethyl)chroman by transphosphatidylation catalyzed by phospholipase D from Streptomyces lydicus [3].
• A novel phosphate ester containing a chromanol structure was synthesized from 1,2-diacyl-sn-glycero-3-phospho-2'-hydroxyethyl-2',5',7',8'-tetramethyl- 6' -hydroxychroman (PCh) by hydrolysis catalyzed by phospholipase C from Bacillus cereus [4].

High impact information on Chromanol

• Chromanol 293B, a specific IKs blocker, dose-dependently (1 to 100 micromol/L) prolonged the QT interval and action potential duration (APD90) of the 3 cell types but did not widen the T wave, increase TDR, or induce TdP [5].
• As described for colonic epithelium, the current through KCNQ1 complexes in murine trachea is specifically inhibited by the chromanol 293B [6].
• Chromanol 293B, an inhibitor of the cAMP-dependent KvLQT1 channel, attenuated the STA(2)-induced Cl- secretion in the human colonic mucosa (IC(50) value 1.18 microm) [7].
• Prevention of APD(90) shortening by chromanol, a selective blocker of I(Ks), was seen in about 40% of myocytes due to short APD in our experimental conditions [8].
• In non-CF tissues, Cl(-) secretion was significantly inhibited by the chromanol 293B (10 micromol/liter), a specific inhibitor of K(V)LQT1 K(+) channels [9].

Biological context of Chromanol

• The lead chromanol 293B specifically inhibited I(sK) channels with an IC50 of 7 micromol/l without affecting the delayed rectifier Kv1.1 or the inward rectifier Kir2 [10].
• In conclusion, new chromanol-type antioxidants, especially twin-chromanol, were able to improve bioenergetic and biochemical parameters of mitochondria exposed to oxidative stress [11].
• Antioxidant properties of natural and synthetic chromanol derivatives: study by fast kinetics and electron spin resonance spectroscopy [12].
• CaCC-dependent ion transport was inhibited by the chromanol 293B, an inhibitor of cAMP-activated hKvLQT1 K+ channels, and by clotrimazole, an inhibitor of Ca2+-activated hSK4 K+ channels [13].
• Pharmacokinetics and metabolism of a cysteinyl leukotriene-1 receptor antagonist from the heterocyclic chromanol series in rats: in vitro-in vivo correlation, gender-related differences, isoform identification, and comparison with metabolism in human hepatic tissue [14].

Anatomical context of Chromanol

• The chromanol derivate 293B blocks currents expressed by minK and not HERG in Xenopus oocytes, but little is known about its effects on native currents and action potentials [15].
• 2. Action potential duration (APD) was minimally increased (less than 7%) by chromanol 293B (10 microM) and L-735,821 (100 nM), selective blockers of IKs, over a range of pacing cycle lengths (300-5000 ms) in both dog right ventricular papillary muscles and Purkinje fibre strands [16].
• Using a pharmacological approach, we found evidence for two types of K+ channels in the mucosal and serosal membranes of HPAF cells, one activated by chlorzoxazone (500 microM) and sensitive to clotrimazole (30 microM), as well as one blocked by clofilium (100 microM) but not chromanol 293B (5 microM) [17].
• Blocking action of chromanol 293B on the slow component of delayed rectifier K(+) current in guinea-pig sino-atrial node cells [18].
• In the present study, novel chromanol-type antioxidants (twin-chromanol, cis- and trans-oxachromanol) as well as the well-known short-chain analogue of alpha-tocopherol, pentamethyl-chromanol, were tested for their antioxidative potency in rat heart mitochondria (RHM) [11].

Associations of Chromanol with other chemical compounds

• 4. In ventricular myocytes, the same concentrations of chromanol 293B (10 microM), L-735,821 (100 nM) and E-4031 (1 microM) markedly or totally blocked I(Ks) and I(Kr), respectively [19].
• The effect of the KCNQ channel blockers XE991, chromanol 293B and linopirdine, was studied on voltage-dependent K+ currents in smooth muscle cells dissociated freshly from mouse portal vein (mPV) and isometric tension recordings from whole mPV [20].
• Cardiac action potential duration was prolonged by antagonists of either ERG1 (MK-499, cisapride) or KCNQ1/KCNE1 (chromanol 293B) [21].
• We hypothesized that blockade of the increased slow IK (IKs) current during beta-adrenergic stimulation could improve action potential prolongation and tested this hypothesis by comparison of three different IK blockers: dofetilide, a selective blocker of IKr; ambasilide, a nonselective blocker of IK; and chromanol 293B, a selective blocker of IKs [22].
• In this study, we generated a guinea pig LQT1 syndrome model using the IKs blocker chromanol 293B and then assayed the electrophysiologic effects of the ATP-sensitive potassium channel IK,ATP opener nicorandil on this model [23].

Gene context of Chromanol

• Chromanol 293B, a blocker of the slow delayed rectifier K+ current (IKs), inhibits the CFTR Cl- current [24].
• The KCNQ1 inhibitor chromanol 293B reversibly depressed IKvol with an IC50 of 26 microM [25].
• The structurally related chromanol 293B (trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chromane), a blocker of the slow component of the delayed rectifier K+ current (IKs) in the heart, is also a weak inhibitor of KATP [24].
• The chromanol, 293B (100 microM), reduced I(SC) by 74%, but charybdotoxin (CTX, 50 nM) had no effect [26].
• Inhibition of IKs in guinea pig cardiac myocytes and guinea pig IsK channels by the chromanol 293B [27].

Analytical, diagnostic and therapeutic context of Chromanol

• We have shown that the KCNQ1 inhibitor chromanol 293B significantly inhibited RVD-associated K(+) flux in isolated perfused rat liver and used patch-clamp techniques to define the signaling pathway linking swelling to I(KVol) activation [28].
• The aim of this study was to determine the contribution of I (Ks) to repolarization in canine ventricular myocytes by measuring the frequency dependent action potential lengthening effect of 10 muM chromanol 293B using sharp microelectrodes [29].

References