In vitro properties of 5-(benzylsulfonyl)-4-bromo-2-methyl-3(2H)-pyridazinone: a novel permeability transition pore inhibitor.
Despite the increasing implication of the permeability transition pore (PTP) in the pathophysiology of neurodegenerative diseases, few selective PTP inhibitors have been reported so far. Here, we evaluate the pharmacological properties of a novel PTP inhibitor, BBMP (5-(benzylsulfonyl)-4-bromo-2-methyl-3(2H)-pyridazinone). This drug was discovered from the screening of a compound library against the PTP using a functional assay with isolated mitochondria. Similarly to cyclosporin A, the drug prevented Ca2+-induced permeability transition and mitochondrial depolarization. BBMP appeared more potent that minocycline in both swelling and membrane potential assays displaying pIC50 values of 5.5+/-0.1 and 5.6+/-0.0, respectively. Unlike minocycline, BBMP dose-dependently prevented DNA fragmentation induced by KCl 25/5 mM shift and serum deprivation in cerebellar granule neurons with a pIC50 of 5.7+/-0.6. The inhibition of PTP-mediated cytochrome c release observed in isolated mitochondria at 10 and 100 microM may explain its neuroprotective properties in vitro. These data suggest that the mitochondrial PTP is potentially involved in neuronal cell death and that PTP inhibitors, like BBMP, may possess a therapeutic potential in neurodegenerative disorders.
Fuks
Bruno
B
UCB, Center for CNS Innovation, Chemin du Foriest, 1420 Braine-l'Alleud, Belgium. bruno.fuks@ucb-group.com
Talaga
Patrice
P
Huart
Catherine
C
Hénichart
Jean-Pierre
JP
Bertrand
Karine
K
Grimée
Renée
R
Lorent
Geneviève
G
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D001593:Benzyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D008911:Minocycline / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000187:drug effects; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
C505033:5-(benzylsulfonyl)-4-bromo-2-methyl-3(2H)-pyridazinone; D000590:Amino Acid Chloromethyl Ketones; D001593:Benzyl Compounds; D061945:Caspase Inhibitors; D016895:Culture Media, Serum-Free; D015853:Cysteine Proteinase Inhibitors; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011724:Pyridazines; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D011189:Potassium Chloride; D016572:Cyclosporine; D045304:Cytochromes c; D008911:Minocycline