Abstract
Recent cardiology research studies have reported the role, function, and structure of the mitochondrial permeability transition pore (mPTP) and have shown that its opening plays a key role in the progression of myocardial cell death secondary to reperfusion. In this manuscript, we validated a new pharmacological approach as an adjunct to reperfusion in myocardial infarction (MI) treatment and describe the discovery, optimization, and structure-activity relationship (SAR) studies of the first small-molecule mPTP opening inhibitors based on a 1,3,8-triazaspiro[4.5]decane scaffold that targets the c subunit of the F1/FO-ATP synthase complex. We identified three potential compounds with good mPTP inhibitory activity and beneficial effects in a model of MI, including a decreased apoptotic rate in the whole heart and overall improvement of cardiac function upon administration during reperfusion. The selected compounds did not show off-target effects at the cellular and mitochondrial levels. Moreover, the compounds preserved the mitochondrial ATP content despite interacting with the ATP synthase complex.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkanes / chemistry
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Animals
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Cardiotonic Agents / chemistry
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Cardiotonic Agents / pharmacology*
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Disease Models, Animal
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Mice
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Mitochondria, Heart / drug effects
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Mitochondria, Heart / metabolism
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Mitochondria, Liver / drug effects
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Mitochondria, Liver / metabolism
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Mitochondrial Membrane Transport Proteins / drug effects
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Mitochondrial Membrane Transport Proteins / metabolism
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Mitochondrial Permeability Transition Pore
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Mitochondrial Proton-Translocating ATPases / antagonists & inhibitors*
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Mitochondrial Proton-Translocating ATPases / metabolism
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Molecular Targeted Therapy
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Myocardial Infarction / complications
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Myocardial Infarction / pathology
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Myocardial Reperfusion Injury / drug therapy*
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Protein Subunits / antagonists & inhibitors
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Rats, Wistar
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Small Molecule Libraries / chemical synthesis
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology
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Structure-Activity Relationship
Substances
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Alkanes
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Cardiotonic Agents
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Enzyme Inhibitors
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Permeability Transition Pore
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Protein Subunits
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Small Molecule Libraries
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F1F0-ATP synthase
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Mitochondrial Proton-Translocating ATPases
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decane