[3H]‐Trimetazidine mitochondrial binding sites: regulation by cations, effect of trimetazidine derivatives and other agents and interaction with an endogenous substance

• Published in: British journal of pharmacology 2000-06, Vol.130 (3), p.655-663
• Main Authors: Morin, Didier, Sapena, Rosa, Elimadi, Aziz, Testa, Bernard, Labidalle, Serge, Le Ridant, Alain, Tillement, Jean‐Paul
• Format: Article
• Language: English
• Subjects: Algorithms; Animals; Antianginal agents. Coronary vasodilator agents; Binding Sites - drug effects; Biological and medical sciences; Brain Chemistry - drug effects; brain mitochondria; Cardiovascular system; Cations - pharmacology; Cytosol - metabolism; Hydrogen-Ion Concentration; In Vitro Techniques; Male; Medical sciences; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Pharmacology. Drug treatments; rat liver mitochondria; Rats; Rats, Wistar; Receptors, Cell Surface - drug effects; specific binding sites; Trimetazidine; Trimetazidine - analogs & derivatives; Trimetazidine - metabolism; Vasodilator Agents - metabolism
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0703348

Trimetazidine, an antiischaemic drug, has been shown to restore impaired mitochondrial functions. Specific binding sites for [3H]‐trimetazidine have been previously detected in liver mitochondria. In the present study we confirm this observation and provide additional evidence for the involvement of these sites in the pharmacological effects of the drug. Inhibition experiments using a series of trimetazidine derivatives revealed the presence of three classes of binding sites. An N‐benzyl substituted analogue of trimetazidine exhibited a very high affinity (Ki=7 nM) for one of these classes of sites. Compounds from different pharmacological classes were evaluated for their ability to inhibit [3H]‐trimetazidine binding. Among the drugs tested pentazocine, ifenprodil, opipramol, perphenazine, haloperidol, and to a lower extent prenylamine, carbetapentane and dextromethorphan competed with high affinity, suggesting a similarity of high affinity [3H]‐trimetazidine sites with sigma receptors. [3H]‐Trimetazidine binding was modulated by pH. Neutral trimetazidine had about 10 fold higher affinity than protonated trimetazidine for its mitochondrial binding sites. Various cations also affected [3H]‐trimetazidine binding. Ca2+ was the most potent inhibitor and totally suppressed the binding of [3H]‐trimetazidine to the sites of medium affinity. An endogenous cytosolic ligand was able to displace [3H]‐trimetazidine from its binding sites. Its activity was not affected by boiling for 15 min, suggesting a non‐protein compound. These data suggest that mitochondrial [3H]‐trimetazidine binding sites could have a physiological relevance and be involved in the antiischaemic effects of the drug. British Journal of Pharmacology (2000) 130, 655–663; doi:10.1038/sj.bjp.0703348