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

1 Trimetazidine, an antiischaemic drug, has been shown to restore impaired mitochondrial functions. Specific binding sites for [H-3]-trimetazidine hav e been previously detected in liver mitochondria. In the present study we c onfirm this observation and provide additional evidence for the involvement of these sites in the pharmacological effects of the drug. 2 Inhibition experiments using a series of trimetazidine derivatives reveal ed the presence of three classes of binding sites. An N-benzyl substituted analogue of trimetazidine exhibited a very high affinity (K-i = 7 nM) for o ne of these classes of sites. 3 Compounds from different pharmacological classes were evaluated for their ability to inhibit [H-3]-trimetazidine binding. Among the drugs tested pen tazocine, ifenprodil, opipramol, perphenazine, haloperidol, and to a lower extent prenylamine, carbetapentane and dextromethorphan competed with high affinity, suggesting a similarity of high affinity [H-3]-trimetazidine site s with sigma receptors. 4 [H-3]-Trimetazidine binding was modulated by pH. Neutral trimetazidine ha d about 10 fold higher affinity than protonated trimetazidine for its mitoc hondrial binding sites. Various cations also affected [3H]-trimetazidine bi nding. Ca2+ was the most potent inhibitor and totally suppressed the bindin g of [H-3]-trimetazidine to the sites of medium affinity. 5 An endogenous cytosolic ligand was able to displace [H-3]-trimetazidine f rom its binding sites. Its activity was not affected by boiling for 15 min, suggesting a non-protein compound. 6 These data suggest that mitochondrial [H-3]-trimetazidine binding sites c ould have a physiological relevance and be involved in the antiischaemic ef fects of the drug.