Article Information

• PDF (989 kb)

PubMed

• Articles by J.Y. Lehtonen
• Articles by P.K. Kinnunen

Related Articles

• Crystal Structure of Human Carboxylesterase 1 Complexed with...

  Crystal Structure of Human Carboxylesterase 1 Complexed with the Alzheimer's Drug Tacrine Chemistry & Biology, Volume 10, Issue 4, 1 April 2003, Pages 341-349 Sompop Bencharit, Christopher L Morton, Janice L Hyatt, Peter Kuhn, Mary K Danks, Philip M Potter and Matthew R Redinbo Summary Human carboxylesterase 1 (hCE1) is a broad-spectrum bioscavenger that plays important roles in narcotic metabolism, clinical prodrug activation, and the processing of fatty acid and cholesterol derivatives. We determined the 2.4 Å crystal structure of hCE1 in complex with tacrine, the first drug approved for treating Alzheimer's disease, and compare this structure to the acetylcholinesterase (AcChE)-tacrine complex. Tacrine binds in multiple orientations within the catalytic gorge of hCE1, while it stacks in the smaller AcChE active site between aromatic side chains. Our results show that hCE1's promiscuous action on distinct substrates is enhanced by its ability to interact with ligands in multiple orientations at once. Further, we use our structure to identify tacrine derivatives that act as low-micromolar inhibitors of hCE1 and may provide new avenues for treating narcotic abuse and cholesterol-related diseases. Summary | Full Text | PDF (483 kb)

• Alzheimer's disease: the tacrine legacy

  Alzheimer's disease: the tacrine legacy Trends in Pharmacological Sciences, Volume 20, Issue 4, 1 April 1999, Pages 127-129 John S Kelly Full Text | PDF (115 kb)

• A preclinical view of cholinesterase inhibitors in neuroprot...

  A preclinical view of cholinesterase inhibitors in neuroprotection: do they provide more than symptomatic benefits in Alzheimer's disease? Trends in Pharmacological Sciences, Volume 26, Issue 2, 1 February 2005, Pages 104-111 Paul T. Francis, Agneta Nordberg and Steven E. Arnold Abstract The prevalence of Alzheimer's disease (AD), a neurodegenerative condition whose greatest risk factor is old age, is expected to rise dramatically during the next five decades, along with the trend for increased longevity. Early diagnosis and intervention with therapies that halt or slow disease progress are likely to represent an important component of effective treatment. Although much progress has been made in this area, there are currently no clinically approved interventions for AD that are classed as disease modifying or neuroprotective. Cholinesterase inhibitors are a drug class used for the symptomatic treatment of AD. Recent evidence from preclinical studies indicates that these agents can attenuate neuronal damage and death from cytotoxic insults, and therefore might affect AD pathogenesis. The mechanisms by which these actions are mediated might or might not be directly related to their primary mode of action. Abstract | Full Text | PDF (249 kb)

• …more

Abstract

Tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrate) is an inhibitor of acetylcholinesterase currently used in the treatment of the symptoms of Alzheimer's disease. The present study demonstrates preferential binding of this drug to acidic phospholipids, as revealed by fluorescence polarization, penetration into lipid monolayers, and effects on the thermal phase behavior of dimyristoyl phosphatidic acid (DMPA). A fivefold enhancement in the polarization of tacrine emission is evident above the main phase transition temperature (T(m)) of DMPA vesicles, whereas below T(m) only a 0.75-fold increase is observed. In contrast, the binding of tacrine to another acidic phospholipid, dimyristoylphosphatidylglycerol, did not exhibit strong dependence on T(m). In accordance with the electrostatic nature of the membrane association of tacrine, the extent of binding was augmented with increasing contents of egg PG in phosphatidylcholine liposomes. Furthermore, [NaCl] > 50 mM dissociates tacrine (albeit incompletely) from the liposomes composed of acidic phospholipids. Inclusion of the cationic amphiphile sphingosine in egg PG vesicles decreased the membrane association of tacrine until at 1:1 sphingosine: egg PG stoichiometry binding was no longer evident. Tacrine also penetrated into egg PG but not into egg PC monolayers. Together with broadening of the main transition and causing a shoulder on its high temperature side, the binding of tacrine to DMPA liposomes results in a concentration-dependent reduction both in the combined enthalpy delta H of the above overlapping endotherms and the main transition temperature T(m). Interestingly, these changes in the thermal phase behavior of DMPA as a function of the content of the drug in vesicles were strongly nonlinear. More specifically, upon increasing [tacrine], T(m) exhibited stepwise decrements. Simultaneously, sharp minima in delta H were observed at drug:lipid stoichiometries of approximately 2:100 and 25:100, whereas a sharp maximum in delta H was evident at 18:100. The above results are in keeping with tacrine causing phase separation processes in the bilayer and may also relate to microscopic drug-induced ordering processes within the membrane.