title: Recognition forces involved in mitochondrial binding to a low-affinity trimetazidine binding site related to anti-ischemic activity.
abstract: 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).
authors: Institut de Chimie Thérapeutique, Section de Pharmacie, Université de Lausanne, Lausanne, Switzerland.
authors: Georgette
authors: G
authors: Plemper van Balen
authors: Pierre Alain
authors: PA
authors: Carrupt
authors: Didier
authors: D
authors: Morin
authors: Jean Paul
authors: JP
authors: Tillement
authors: Alain
authors: A
authors: Le Ridant
authors: Bernard
authors: B
authors: Testa
mesh_terms: D000818:Animals; D001665:Binding Sites; D004337:Drug Carriers; D007511:Ischemia / Q000517:prevention & control; D008081:Liposomes; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008933:Mitochondrial Swelling / Q000187:drug effects; D014292:Trimetazidine / Q000494:pharmacology* / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D014665:Vasodilator Agents; D014292:Trimetazidine