title: Cytochrome P450 binding studies of novel tacrine derivatives: Predicting the risk of hepatotoxicity.
abstract: The 1,2,3,4-tetrahydroacridine derivative tacrine was the first drug approved to treat Alzheimer's disease (AD). It is known to act as a potent cholinesterase inhibitor. However, tacrine was removed from the market due to its hepatotoxicity concerns as it undergoes metabolism to toxic quinonemethide species through the cytochrome P450 enzyme CYP1A2. Despite these challenges, tacrine serves as a useful template in the development of novel multi-targeting anti-AD agents. In this regard, we sought to evaluate the risk of hepatotoxicity in a series of C9 substituted tacrine derivatives that exhibit cholinesterase inhibition properties. The hepatotoxic potential of tacrine derivatives was evaluated using recombinant cytochrome (CYP) P450 CYP1A2 and CYP3A4 enzymes. Molecular docking studies were conducted to predict their binding modes and potential risk of forming hepatotoxic metabolites. Tacrine derivatives compound 1 (N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) and 2 (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) which possess a C9 3,4-dimethoxybenzylamino substituent exhibited weak binding to CYP1A2 enzyme (1, IC50=33.0µM; 2, IC50=8.5µM) compared to tacrine (CYP1A2 IC50=1.5µM). Modeling studies show that the presence of a bulky 3,4-dimethoxybenzylamino C9 substituent prevents the orientation of the 1,2,3,4-tetrahydroacridine ring close to the heme-iron center of CYP1A2 thereby reducing the risk of forming hepatotoxic species.
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Alanna
authors.initials: A
authors.lastname: McEneny-King
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Wesseem
authors.initials: W
authors.lastname: Osman
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Edginton
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada. Electronic address: praopera@uwaterloo.ca.
authors.forename: Praveen P N
authors.initials: PPN
authors.lastname: Rao
mesh_terms: D001571:Benzoflavones / Q000737:chemistry; D001665:Binding Sites; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry; D065609:Cytochrome P-450 CYP1A2 Inhibitors / Q000737:chemistry*; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000737:chemistry*; D006801:Humans; D007654:Ketoconazole / Q000737:chemistry; D062105:Molecular Docking Simulation; D012306:Risk; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry*
chemical_list: D001571:Benzoflavones; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D013619:Tacrine; C011512:alpha-naphthoflavone; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole
keywords: 3,4-Dimethoxybenzylamino; CYP1A2; CYP3A4; Cholinesterase inhibitors; Cytochrome P450; Hepatotoxicity; Molecular docking; Tacrine