Novel cobalt complex inhibitors of mitochondrial calcium uptake

Reperfusion of the ischaemic myocardium leads to intracellular calcium overload followed by mitochondrial dysfunction, resulting in insufficient energy supply and ultimately myocardial necrosis. Ruthenium red (RR), a potent mitochondrial calcium uptake inhibitor, prevents this disruption to mitochon...

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Bibliographic Details
Published inBioorganic & medicinal chemistry Vol. 7; no. 9; pp. 1891 - 1896
Main Authors UNITT, J. F, BODEN, K. L, WALLACE, A. V, INGALL, A. H, COOMBS, M. E, INCE, F
Format Journal Article
LanguageEnglish
Published Oxford Elsevier Science 01.09.1999
Subjects
Animals
Biological and medical sciences
Calcium - metabolism
Cardiovascular system
Cobalt - chemistry
Ethylenediamines - chemistry
Ethylenediamines - pharmacology
Intracellular Membranes - drug effects
Intracellular Membranes - metabolism
Intracellular Membranes - physiology
Ion Transport
Medical sciences
Membrane Potentials - drug effects
Miscellaneous
Mitochondria, Heart - drug effects
Mitochondria, Heart - metabolism
Organometallic Compounds - chemistry
Organometallic Compounds - pharmacology
Pharmacology. Drug treatments
Rats
Structure-Activity Relationship
Heart
Cobalt Complexes
Calcium
Organic ligand
Ion transport
Transition metal Complexes
Trivalent metal Complexes
Reuptake inhibitor
In vitro
Mitochondria
Structure activity relation
Dinuclear complex
Membrane potential
Chemical synthesis
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Summary:Reperfusion of the ischaemic myocardium leads to intracellular calcium overload followed by mitochondrial dysfunction, resulting in insufficient energy supply and ultimately myocardial necrosis. Ruthenium red (RR), a potent mitochondrial calcium uptake inhibitor, prevents this disruption to mitochondrial metabolism and improves post reperfusion recovery. This therefore suggested that mitochondrial calcium influx is an attractive target for the treatment of reperfusion injury. However, RR is unsuitable for therapeutic use, so we undertook a search for novel compounds which inhibit mitochondrial calcium uptake. The most potent compounds discovered were simple tris(ethylenediamine) transition metal complexes and dinuclear Co complexes. The structure-activity relationship (SAR) of these small molecules has helped to define the structural requirements for inhibition of calcium transport by outlining the size and charge dependency of the interactive site on the mitochondrial calcium uniporter.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(99)00166-2