Recognition forces involved in mitochondrial binding to a low-affinity trimetazidine binding site related to anti-ischemic activity

A number of heterogeneous drugs previously shown to bind to trimetazidine (TMZ) binding sites on mitochondria and to inhibit mitochondrial swelling (Morin et al., Br J Pharmacol 1998;123:1385-94) were investigated here for their physicochemical properties. The molecular parameters measured were the partition coefficients of the neutral and monocationic forms in the n-octanol/water and dichloroethane/water systems, their distribution coefficients at pH 7.4 in these two solvent systems, as well as their distribution coefficients at pH 7.4 in a phosphatidylcholine (PhC) liposomes/water system (log D-lip(7.4)). Most of these properties were not correlated with affinity to mitochondria or inhibition of mitochondrial swelling. In contrast, log D-lip(7.4) showed a modest correlation with binding to the low-affinity site (r(2) = 0.52) and a better correlation with anti-swelling activity (r(2) = 0.69), itself well correlated with binding to the low-affinity sites (r(2) = 0.83). Thus, these sites have recognition properties much like those of membranes, as they depend on lipophilicity-hydrophobicity (core binding) and ionic bonds (surface interactions). (C) 2002 Elsevier Science Inc. All rights reserved.