The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cAMP-activated epithelial Cl- channel. GlyH-101 is a glycine hydrazide compound that inhibits CFTR with a Ki value of 4.3±0.9μM. The inhibitory potency of GlyH-101 against CFTR was reduced at more negative voltages, with Ki values of 1.4, 3.8, 5.0, and 5.6μM for voltages of +60, +20, −20, and −60mV, respectively.[3] GlyH-101 inhibited cAMP/PKA-activated Cl- current in a dose- and voltage-dependent manner with IC50 values of 0.3±1.5 and 5.1±1.3μM at +100 and −100mV, respectively.[4] GlyH-101 at a dosage of 10μM rapidly and reversibly inhibited forskolin-induced hyperpolarization in nasal potential differences in mice (CD1 strain).[3]
作用机制
The inhibition of CFTR by GlyH-101 involves direct CFTR pore occlusion at a site at or near the extracellular-facing pore surface.[3]
GlyH-101 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Rat pancreatic explants
10 μmol/l
1-7 days
GlyH-101 increased the absolute number of NGN3+ endocrine progenitors and the number of beta cells, as well as the expression of insulin and Mafa.
GlyH-101 blocked more than 70% of the CaCC conductance at 10 µM.
Br J Pharmacol. 2014 Aug;171(15):3716-27.
PS120 cells (non-CFTR expressing)
0.5, 1, 5, 10 µM
GlyH-101 significantly inhibited VSORC currents with IC50 values of approximately 5.38 µM (negative potentials) and 6.26 µM (positive potentials).
Br J Pharmacol. 2014 Aug;171(15):3716-27.
Murine renal distal convoluted tubule cells (DCT)
0.5, 1, 5, 10 µM
GlyH-101 induced a concentration-dependent inhibition of the CFTR-like current, with almost complete inhibition at 10 µM and a more pronounced effect at positive potentials.
Br J Pharmacol. 2014 Aug;171(15):3716-27.
Mouse beta-cells
50 μM
10 minutes
To investigate the effect of GlyH-101 on cAMP-enhanced insulin secretion, results showed that GlyH-101 significantly inhibited cAMP-enhanced insulin secretion.
BMC Med. 2014 May 28;12:87.
Human beta-cells
50 μM
10 minutes
To investigate the effect of GlyH-101 on cAMP-enhanced insulin secretion, results showed that GlyH-101 significantly inhibited cAMP-enhanced insulin secretion.
BMC Med. 2014 May 28;12:87.
Calu-3KD cells
50 μM
30 minutes
GlyH-101 partially inhibited CFTR channel activity in Calu-3KD cells, but responses to lubiprostone and CCh were retained.
Br J Pharmacol. 2007 Apr;150(8):1055-65.
Calu-3WT cells
50 μM
30 minutes
GlyH-101 completely inhibited CFTR channel activity in Calu-3WT cells, resulting in no response to lubiprostone or CCh.
Br J Pharmacol. 2007 Apr;150(8):1055-65.
Human airway smooth-muscle cells
2 μM
5 hours
To evaluate the effects of GlyH-101 on cellular sphingolipid composition. Results showed GlyH-101 increased sphinganine and dihydroceramides.
Am J Respir Cell Mol Biol. 2020 Nov;63(5):690-698.
Human alveolar epithelial cell line A549
2 μM
5 hours
To evaluate the effects of GlyH-101 on cellular sphingolipid composition. Results showed GlyH-101 increased sphinganine and dihydroceramides.
Am J Respir Cell Mol Biol. 2020 Nov;63(5):690-698.
Calu-3 cells
10 μM
GlyH-101 had no effect on the mean alkalinization produced by the removal of basolateral Cl- under non-stimulated conditions, but in the presence of GlyH-101, the cAMP agonist forskolin failed to fully inhibit the basolateral exchanger
Br J Pharmacol. 2013 Apr;168(8):1946-60.
Normal Human Bronchial Epithelial cells (NHBE)
10 μM
20-50 minutes
GlyH-101 significantly blocked H2O2-induced CFTR-dependent current changes
Am J Respir Cell Mol Biol. 2013 Oct;49(4):672-9.
GlyH-101 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Pregnant E12.5 mice
Subcutaneous injection
10 mg/kg
Twice daily for six consecutive days
GlyH-101 increased the surface area of insulin+ and glucagon+ cells in E18.5 pancreases but did not modify beta cell proliferation.
Diabetologia. 2013 Feb;56(2):330-9.
Mice
SPT-deficient mice
Intratracheal administration
80 mg/kg
Single dose, evaluated after 4 hours
To evaluate the effects of GlyH-101 on airway hyperreactivity. Results showed GlyH-101 decreased AHR in SPT-deficient mice.
Am J Respir Cell Mol Biol. 2020 Nov;63(5):690-698.
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