Identification of arylsulfonamides as Aquaporin 4 inhibitors

Huber, Vincent J.; Teräs, Mika; Yamazaki, Maya; Sakimura, Kenji; Nakada, Tsutomu

doi:10.1016/j.bmcl.2006.12.010

Cited by 130 publications

(120 citation statements)

References 23 publications

Supporting

Mentioning

117

Contrasting

Order By: Relevance

“…The IC 50 of AZA's inhibition of human AQP4-M23-mediated water transport is 0.9 μmol/L, and the reported maximum inhibition of AQP4-M23 by AZA is 85% [23] . AQP4 is mainly expressed in glial cells, which are activated in chronic pain but not in acute pain.…”

Section: Discussionmentioning

confidence: 92%

See 1 more Smart Citation

Acetazolamide attenuates chemical-stimulated but not thermal-stimulated acute pain in mice

Sun

Chen²,

Peng³

et al. 2013

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: Acetazolamide (AZA), a carbonic anhydrase (CA) inhibitor, has been found to alleviate inflammatory and neuropathic pain in rats. In the present study, we investigated the effects of AZA on thermal-and chemical-stimulated acute pain in mice and the possible mechanisms underlying the effects. Methods: Five acute pain models based on thermal and chemical stimuli were established to investigate the effects of AZA on different types of nociception in mice. The antinociceptive effects of methazolamide (another CA inhibitor) and diazepam (a positive allosteric modulator of GABA A receptor) were also examined. The drugs were administered either intraperitoneally (ip) or intrathecally. Results: AZA (50-200 mg/kg, ip) did not produce analgesia in two thermal-stimulated acute pain models, ie, mouse tail-flick and hotplate tests. In contrast, AZA (50-200 mg/kg, ip) dose-dependently reduced paw licking time in both capsaicin and formalin tests in mice. A similar result was observed in a mouse acetic acid-induced writhing test. However, AZA (10 nmol/mouse, intrathecally) did not produce significant analgesia in the 3 chemical-stimulated acute pain models. In addition, methazolamide (50-200 mg/kg, ip) and diazepam (0.25-1.0 mg/kg, ip) did not produce significant analgesia in either thermal-or chemical-stimulated acute pain. Conclusion: AZA produces analgesia in chemical-stimulated, but not thermal-stimulated acute pain in mice. The attenuation of chemical-stimulated acute pain by AZA may not be due to enhancement of GABA A receptor-mediated inhibition via inhibiting CA activity but rather a peripheral ion channel-related mechanism.

show abstract

Section: Discussionmentioning

confidence: 92%

“…In addition to acting as a CA inhibitor, AZA is a non-selective inhibitor of aquaporin 4 (AQP4) [23][24][25] . The IC 50 of AZA's inhibition of human AQP4-M23-mediated water transport is 0.9 μmol/L, and the reported maximum inhibition of AQP4-M23 by AZA is 85% [23] .…”

Section: Discussionmentioning

confidence: 99%

Acetazolamide attenuates chemical-stimulated but not thermal-stimulated acute pain in mice

Sun

Chen²,

Peng³

et al. 2013

Acta Pharmacol Sin

View full text Add to dashboard Cite

show abstract

“…Recently, three papers from one laboratory reported AQP4 inhibition by a series of arylsulfonamides, antiepileptic drugs, and related molecules, with strong inhibition at low micromolar concentrations [8][9][10] . The rationale for their investigation of arylsulfonamides, such as acetazolamide, was reports suggesting acetazolamide inhibition of a different water channel, AQP1 [11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides

Yang

Zhang

Verkman

2008

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

Inhibitors of brain glial water channel aquaporin-4 (AQP4) are of potential clinical utility, as they are predicted to modulate brain edema, neuroexcitation and glial scarring. Recently, Huber et al. (Bioorgan. Med. Chem. 2007, 17:1270 2008, in press) reported that a series of arylsulfomamides, antiepileptics, and related small molecules strongly inhibited AQP4 water transport with IC50s down to 1 μM. We retested the compounds with greatest reported potencies, including acetylsulfanilamide, acetazolamide, 6-ethoxy-benzothiazole-2-sulfonamide, topiramate, zonisamide, phenytoin, lamotrigine and sumatriptan, in AQP4-transfected mammalian cells and primary cultures of brain glial cells, using several sensitive assays of osmotic water permeability. Contrary to the findings of Huber et al., in our studies we found no significant inhibition of AQP4 water permeability by any of the compounds at concentrations up to 100 μM.

show abstract

“…Because of its role, inhibitors of AQP4 are sought, although so far with conflicting results. Certain quaternary ammonium compounds (6), antiepileptic drugs (7,8), and serotonin receptor agonists (9) have been reported to inhibit AQP4 water transport in oocytes with IC 50 values down to the low micromolar range. However, Yang et al (10) report no inhibition up to 100 M using different assay methods.…”

Section: T He Aquaporin (Aqp) Family Includes Both Aqps That Conductmentioning

confidence: 99%

Crystal structure of human aquaporin 4 at 1.8 Å and its mechanism of conductance

Yeh

Sandstrom

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

305

291

View full text Add to dashboard Cite

Aquaporin (AQP) 4 is the predominant water channel in the mammalian brain, abundantly expressed in the blood-brain and braincerebrospinal fluid interfaces of glial cells. Its function in cerebral water balance has implications in neuropathological disorders, including brain edema, stroke, and head injuries. The 1.8-Å crystal structure reveals the molecular basis for the water selectivity of the channel. Unlike the case in the structures of water-selective AQPs AqpZ and AQP1, the asparagines of the 2 Asn-Pro-Ala motifs do not hydrogen bond to the same water molecule; instead, they bond to 2 different water molecules in the center of the channel. Molecular dynamics simulations were performed to ask how this observation bears on the proposed mechanisms for how AQPs remain totally insulating to any proton conductance while maintaining a single file of hydrogen bonded water molecules throughout the channel.brain edema ͉ inhibitor discovery ͉ NPA motif

show abstract

Identification of arylsulfonamides as Aquaporin 4 inhibitors

Cited by 130 publications

References 23 publications

Acetazolamide attenuates chemical-stimulated but not thermal-stimulated acute pain in mice

Acetazolamide attenuates chemical-stimulated but not thermal-stimulated acute pain in mice

Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides

Crystal structure of human aquaporin 4 at 1.8 Å and its mechanism of conductance

Contact Info

Product

Resources

About