Chloride channels represent a relatively under-explored target class for drug discovery as elucidation of their identity and physiological roles has lagged behind that of many other drug targets. Chloride channels are involved in a wide range of biological functions, including epithelial fluid secretion, cell-volume regulation, neuroexcitation, smooth-muscle contraction and acidification of intracellular organelles. Mutations in several chloride channels cause human diseases, including cystic fibrosis, macular degeneration, myotonia, kidney stones, renal salt wasting and hyperekplexia. Chloride-channel modulators have potential applications in the treatment of some of these disorders, as well as in secretory diarrhoeas, polycystic kidney disease, osteoporosis and hypertension.
Chloride channel accessory proteins, also known as calcium-activated chloride channel regulators (CLCA proteins), are a family of transmembrane proteins that have been suggested to have a role in chloride conductance in epithelial cells.
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A potent analog of lonidamine known to disrupt germ cell adhesion, a potential candidate for male contraceptive development; targets actin filament bundles at the apical ES, blocks the expression of PAR6 and 14-3-3 (also known as PAR5); also induces apoptosis in cancer cells through a Caspase-3-dependent pathway; inhibited LPS-induced IL-6 release and IL-6, IL-1β, TNF-α expression in BV2 microglial cells.
Chlorotoxin is a 36-amino acid peptide found in the venom of the deathstalker scorpion (Leiurus quinquestriatus); blocks small-conductance chloride channels.
CLP290 (CLP-290) is an orally acirtve small molecule K+-Cl- cotransporter isotype 2 (KCC2) activator, the carbamate prodrug of CLP257; In vivo co-treatment with morphine and oral CLP290 prevented membrane KCC2 downregulation in SDH neurons. Concurrently, co-treatment with CLP290 significantly mitigated MIH and acute administration of CLP257 in established MIH restored normal nociceptive behavior.
T16Ainh-A01 is an inhibitor of the calcium-activated chloride channel TMEM16A, inhibits Ca2+-activated Cl− channel (CACC) activity in TMEM16A-transfected FRT cells with IC50 of 1 uM; T16Ainh-A01 (1-30 uM) inhibited single calcium (Ca2+)-activated chloride (Cl−) channels and whole cell currents activated by 500 nM free Ca2+; T16Ainh-A01 relaxed mouse thoracic aorta pre-contracted with methoxamine with an IC50 of 1.6 uM and suppressed the methoxamine concentration-effect curve; blocks calcium-activated chloride channels in vascular smooth muscle cells and relaxes murine and human blood vessels.
CLP257 (CLP-257) is a potent, selective K+-Cl- cotransporter KCC2 activator with EC50 of 616 nM; displays selectivity for KCC2 over other KCC family members, NKCC1 and GABAA receptors, and a panel of 55 other receptors; restores impaired Cl(-) transport in neurons, rescues KCC2 plasma membrane expression; renormalizes stimulus-evoked responses in spinal nociceptive pathways in a rat model of neuropathic pain.
VU 0463271 is a potent, selecitve inhibitor of the neuronal K-Cl cotransporter KCC2 with IC50 of 61 nM; displays >100-fold selectivity versus NKCC1 (>100 uM), no significant activities on a panel of 68 GPCRs, ion channels and transporters; exhibts 9-times more potent than ML077, and maintains an excellent ancillary pharmacology profile.
IAA-94 is an indanyloxyacetic acid (IAA) inhibitor of epithelial chloride channels that binds channels in bovine kidney cortex microsomes with Ki of 1 uM; significantly suppresses IGF-I-induced VSMC proliferation, also blocks cell swelling evoked glutamate release from primary microglia and MLS-9 cells; effectively reduces IFNgamma-induced NO production in microglial BV2 cells.
OADS is a specific, reversible, small-molecule inhibitor directs against CLC (Chloride Channel) antiporter with Ki of 29 uM, has no specific effect on a CLC channel (ClC-1).
DRAinh-A250 is a specific inhibitor of Cl-/anion exchanger SLC26A3 (DRA), fully and reversibly inhibits SLC26A3-mediated Cl- exchange with HCO3-, I-, and thiocyanate (SCN-) with IC50 of ~0.2 uM; does not inhibit the homologous anion exchangers SLC26A4 (pendrin) or SLC26A6 (PAT-1), as well as other related proteins or intestinal ion channels; blocked fluid absorption in closed colonic loops but not in jejunal loops in mice, while the NHE3 (SLC9A3) inhibitor tenapanor blocked absorption only in the jejunum; reduces signs of constipation in loperamide-treated mice after oral treatment.
VU 0240551 is a potent, selecticve inhibitor of the neuronal K-Cl cotransporter KCC2 with IC50 of 568 nM in K+ uptake assay in KCC2-overexpressing cells; displays >100-fold selectivity over NKCCl; also shows significant inhibition (>50% at 50 µM) of several GPCRs and key ion channels (hERG and L-Type Ca2+ channels).
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