Molecular Pharmacology

Novel cyclophilin D inhibitors derived from quinoxaline exhibit highly inhibitory activity against rat mitochondrial swelling and Ca2+ uptake/release



To investigate methods for identifying specific cyclophilin D (CypD) inhibitors derived from quinoxaline, thus developing possible lead compounds to inhibit mitochondrial permeability transition (MPT) pore opening.


Kinetic analysis of the CypD/inhibitor interaction was quantitatively performed by using surface plasmon resonance (SPR) and fluorescence titration (FT) techniques. IC50 values of these inhibitors were determined by PPIase inhibition activity assays.


All the equilibrium dissociation constants (KD) of the seven compounds binding to CypD were below 10 μmol/L. The IC50 values were all consistent with the SPR and FT results. Compounds GW2, 5, 6, and 7 had high inhibition activities against Ca2+-dependent rat liver mitochondrial swelling and Ca2+ uptake/release. Compound GW5 had binding selectivity for CypD over CypA.


The agreement between the measured IC50 values and the results of SPR and FT suggests that these methods are appropriate and powerful methods for identifying CypD inhibitors. The compounds we screened using these methods (GW1-7) are reasonable CypD inhibitors. Its potent ability to inhibit mitochondrial swelling and the binding selectivity of GW5 indicates that GW5 could potentially be used for inhibiting MPT pore opening.


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Corresponding authors

Correspondence to Xu Shen or Hua-liang Jiang.

Additional information

Project supported by the State Key Program for Basic Research of China (No 2004CB-518905), the National High Technology Research and Development Program of China (No 2002AA33011 and 2005AA235030), the National Natural Science Foundation of China (No 20372069 and 20472095), and the Shanghai Basic Research Project from the Shanghai Science and Technology Commission (No 03DZ19212 and 03DZ19228).

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Guo, Hx., Wang, F., Yu, Kq. et al. Novel cyclophilin D inhibitors derived from quinoxaline exhibit highly inhibitory activity against rat mitochondrial swelling and Ca2+ uptake/release. Acta Pharmacol Sin 26, 1201–1211 (2005).

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  • cyclophilin
  • quinoxalines
  • surface plasmon resonance
  • mitochondrial permeability transition
  • fluorescence titration
  • inhibitor

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