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7143-09-1Relevant articles and documents
Reaction mechanism for cocaine esterase-catalyzed hydrolyses of (+)- and (-)-cocaine: Unexpected common rate-determining step
Liu, Junjun,Zhao, Xinyun,Yang, Wenchao,Zhan, Chang-Guo
experimental part, p. 5017 - 5025 (2011/06/19)
First-principles quantum mechanical/molecular mechanical free energy calculations have been performed to examine the catalytic mechanism for cocaine esterase (CocE)-catalyzed hydrolysis of (+)-cocaine in comparison with CocE-catalyzed hydrolysis of (-)-cocaine. It has been shown that the acylation of (+)-cocaine consists of nucleophilic attack of the hydroxyl group of Ser117 on the carbonyl carbon of (+)-cocaine benzoyl ester and the dissociation of (+)-cocaine benzoyl ester. The first reaction step of deacylation of (+)-cocaine, which is identical to that of (-)-cocaine, is rate-determining, indicating that CocE-catalyzed hydrolyses of (+)- and (-)-cocaine have a common rate-determining step. The computational results predict that the catalytic rate constant of CocE against (+)-cocaine should be the same as that of CocE against (-)-cocaine, in contrast with the remarkable difference between human butyrylcholinesterase-catalyzed hydrolyses of (+)- and (-)-cocaine. The prediction has been confirmed by experimental kinetic analysis on CocE-catalyzed hydrolysis of (+)-cocaine in comparison with CocE-catalyzed hydrolysis of (-)-cocaine. The determined common rate-determining step indicates that rational design of a high-activity mutant of CocE should be focused on the first reaction step of the deacylation. Furthermore, the obtained mechanistic insights into the detailed differences in the acylation between the (+)- and (-)-cocaine hydrolyses provide indirect clues for rational design of amino acid mutations that could more favorably stabilize the rate-determining transition state in the deacylation and, thus, improve the catalytic activity of CocE. This study provides a valuable mechanistic base for rational design of an improved esterase for therapeutic treatment of cocaine abuse.
Synthesis, properties, and reactivity of cocaine benzoylthio ester possessing the cocaine absolute configuration
Isomura, Shigeki,Hoffman, Timothy Z.,Wirsching, Peter,Janda, Kim D.
, p. 3661 - 3668 (2007/10/03)
One aspect of immunopharmacotherapy for cocaine abuse involves the use of a catalytic monoclonal antibody (mAb) to degrade cocaine via hydrolysis of the benzoate ester. A cocaine benzoylthio ester analogue provides a means to implement high-throughput selection strategies to potentially isolate mAbs with high activity. The required analogue was synthesized starting from (-)-cocaine hydrochloride and possessed the cocaine absolute configuration. Key points in the preparation were the introduction of the sulfur atom at C-3 via a bromomagnesium thiolate addition to the exo face of anhydroecgonine, separation of C-2 diastereomers, recycling of a C-2 thio ester byproduct, and formation of the necessary C-2 methyl and C-3 benzoylthio esters. Effects resulting from the lower electronegativity and greater hydrophobicity of sulfur compared to oxygen were observed. These characteristics could result in interesting drug properties. Furthermore, the analogue was found to be a substrate for catalytic mAbs that hydrolyze cocaine as monitored by HPLC and also spectrophotometry by coupling cleavage of the benzoylthio ester to the disulfide exchange with Ellman's reagent. Screening antibody libraries with the new cocaine analogue using the spectroscopic assay provides an avenue for the high-throughput identification of catalysts that efficiently breakdown cocaine.
Cocaine catalytic antibodies: The primary importance of linker effects
Matsushita, Masayuki,Hoffman, Timothy Z.,Ashley, Jon A.,Zhou, Bin,Wirsching, Peter,Janda, Kim D.
, p. 87 - 90 (2007/10/03)
Current treatments for cocaine addiction are not effective. The development of a catalytic monoclonal antibody (mAb) provides a strategy for not only binding, but also degrading cocaine, which offers a broad-based therapy. Hapten design is the central element for programming antibody catalysis. The characteristics of the linker used in classic transition-state analogue phosphonate haptens were shown to be important for obtaining mAbs that hydrolyze the benzoate ester of cocaine.
Nonenzymatic hydrolysis of cocaine via intramolecular acid catalysis
Li, Pan,Zhao, Kang,Deng, Shixian,Landry, Donald W.
, p. 85 - 89 (2007/10/03)
The spontaneous hydrolysis of the methyl-ester group of cocaine (1) in vivo contributes to the metabolic clearance of the drug in man. Neighboring- group participation by the tropane N-atom of cocaine in this hydrolysis was suggested by the normal stability of the methyl-ester groups of pseudococaine and N-acylnorcocaine. For cocaine, the relative rate of methyl-ester to benzoyl-ester hydrolysis was ca. 10:1 at pH ≤ 7.4, and, although absolute rates increased with increasing pH, their ratio collapsed at pH > pK(a) (8.6). These data are consistent with intramolecular acid catalysis of alkaline hydrolysis of the cocaine methyl-ester group under physiologic conditions.
Two-carbon bridge substituted cocaines: Enantioselective synthesis, attribution of the absolute configuration and biological activity of novel 6- and 7-methoxylated cocaines
Simoni, Daniele,Roberti, Marinella,Andrisano, Vincenza,Manferdini, Monica,Rondanin, Riccardo,Invidiata, Francesco Paolo
, p. 275 - 287 (2007/10/03)
In an effort to learn more about the general structure-activity relationships of cocaine with the aim to elucidate those structural features that might confer antagonistic properties to such analogues, we describe herein our synthetic efforts to prepare two-carbon bridge functionalized (methoxylated and hydroxylated) analogues. Our approach makes use of a modification of the classical Willstatter synthesis of cocaine: Mannich type cyclization of acetonedicarboxylic acid monomethyl ester with methylamine hydrochloride and 2-methoxysuccindialdehyde in a citrate buffer solution afforded the 6- and 7-substituted 2-carbomethoxy-3-tropinones 3a,b and 4a,b in approximate yields of 64%. Reduction of the (±)-tropinone derivatives was performed with sodium amalgam in a sulfuric acid solution to afford a mixture of (±)-methoxyecgonine and (±)-methoxypseudoecgonine derivatives 5, 11 and 6, 7, 12, 13. Benzoylation of these alcohols yielded the desired cocaine and pseudococaine-like compounds 8, 14 and 9, 10, 15, 16. Additionally, we show that enzymatic hydrolysis of these cocaine analogues using pig liver esterase (PLE) affords a practical means for achieving their chemical resolution. The enantiomers of the methoxycocaine analogues were also prepared starting from chiral (±)- and(-)-6-methoxytropinone. All new analogues were examined for their ability to displace [3H]mazindol binding and to inhibit high-affinity uptake of [3H]dopamine into striatal nerve ending (synaptosomes). It appeared evident that methoxylation of the cocaine two-carbon bridge provides compounds of particular interest: the K(i) for the binding of the methoxypseudococaines is about two to four times smaller than the K(i) for inhibition of dopamine uptake, thus enabling these compounds capable of countering the effects of cocaine to some extent.
An improved cocaine hydrolase: The A328Y mutant of human butyrylcholinesterase is 4-fold more efficient
Xie, Weihua,Altamirano, Cibby Varkey,Bartels, Cynthia F.,Speirs, Robert J.,Cashman, John R.,Lockridge, Oksana
, p. 83 - 91 (2007/10/03)
Butyrylcholinesterase (BChE) has a major role in cocaine detoxication. The rate at which human BChE hydrolyzes cocaine is slow, with ak(cat) of 3.9 min-1 and K(m) of 14 μM. Our goal was to improve cocaine hydrolase activity by mutating residues near the active site. The mutant A328Y had a k(cat) of 10.2 min-1 and K(m) of 9 μM for a 4-fold improvement in catalytic efficiency (k(cat)/Km). Since benzoylcholine (k(cat) 15,000 min- 1) and cocaine form the same acyl-enzyme intermediate but are hydrolyzed at 4000-fold different rates, it was concluded that a step leading to formation of the acyl-enzyme intermediate was rate-limiting. BChE purified from plasma of cat, horse, and chicken was tested for cocaine hydrolase activity. Compared with human BChE, horse BChE had a 2-fold higher k(cat) but a lower binding affinity, cat BChE was similar to human, and chicken BChE had only 10% of the catalytic efficiency. Naturally occurring genetic variants of human BChE were tested for cocane hydrolase activity. The J and K variants (E497V and A539T) had k(cat) and K(m) values similar to wild type, but because these variants are reduced to 66 and 33% of normal levelsin human blood respectively, people with these variants may be at risk for cocaine toxicity. The atypical variant (D70G) had a 10 fold lower binding affinity for cocaine, suggesting that persons with the atypical variant of BChE may experience severe or fatal cocaine intoxication when administered a dose of cocaine that is not harmful to others.
Cocaine and butyrylcholinesterase (BChE): Determination of enzymatic parameters
Mattes, Carol,Bradley,Slaughter,Browne
, p. 257 - 261 (2007/10/03)
In humans, the plasma enzyme, butyrylcholinesterase (E.C. 3.1.1.8), metabolizes cocaine to the water-soluble, pharmacologically inactive compounds, ecgonine methylester and benzoic acid. Homogenous enzyme was purified from human plasma and used to determine the enzyme kinetic parameters of Km and Vmax with cocaine as the substrate. The KM (11.9 μM) indicates that cocaine is tightly bound to the four active sites of the native tetramer. The Vmax (1.17 μM/min) is 50-fold greater than cocaine catalytic antibodies. Administration of purified human butyrylcholinesterase to a cocaine-intoxicated patient would be expected to shift the metabolism to the inactive metabolites and reduce the toxicity.
A PLE-based resolution of cocaine, pseudococaine, and 6-and 7-methoxylated cocaine analogues
Kozikowski,Simoni,Baraldi,Lampronti,Manfredini
, p. 441 - 444 (2007/10/03)
The enzymatic hydrolysis of racemic cocaine and cocaine analogues using pig liver esterase (PLE) is shown to afford a practical means for achieving their chemical resolution. This reaction was found to proceed not only with good enantioselectivity, but with an interesting chemoselectivity as well.
Stereoselective deprotonation of tropinone and reactions of tropinone lithium enolate
Majewski, Marek,Zheng, Guo-Zhu
, p. 2618 - 2626 (2007/10/02)
Tropinone (6) was deprotonated with lithium diisopropylamide and with chiral lithium amides (18-24) and the resulting enolates (two enantiomers) were treated with electrophiles.The aldol reaction with benzaldehyde and deuteration were both diastereoselective.The former yielded only one isomer (exo, anti) of the aldol 8a; the latter proceeded from the exo face.This selectivity permitted us to probe the deprotonation of tropinone with lithium amides; it was concluded that the reaction involves predominantly the exo axial protons.The reaction of tropinone enolate with ethyl chloroformate led, via a ring opening, to the cycloheptenone derivative 9.The reaction with methyl cyanoformate yielded, in the presence of silver acetate and acetic acid, the β-ketoester 8b; however, in the absence of these additives, and especially when 12-crown-4 was added to the enolate, a ring opening leading to the pyrrolidine derivative 10 occured instead.Deprotonation of tropinone with chiral amides proceeded with modest enantioselectivity.A synthesis of non-racemic anhydroecgonine via this strategy allowed establishing the absolute stereochemistry of deprotonation.
Prediction of stability in pharmaceutical preparations. XX: Stability evaluation and bioanalysis of cocaine and benzoylecgonine by high-performance liquid chromatography
Garrett,Seyda
, p. 258 - 271 (2007/10/02)
Specific, sensitive, reverse-phase high-performance liquid chromatographic (HPLC) assays of cocaine (I) and its hydrolysis products, benzoylecgonine (II) and benzoic acid (III), have been devised with analytical sensitivities as low as 15 ng/ml of plasma for I using spectrophotometric detection at 232 nm. Cocaine can be separated from its hydrolysis products by extraction at pH 7.5 with haloalkanes. Benzoylecgonine and benzoic acid can be extracted at pH 3.0 with 1-butanol. The evaporated residues were reconstituted in acetonitrile-water for HPLC assay. The assay was used to determine the stabilities of I and II in aqueous solutions, to establish log k-pH profiles at various temperatures, and to evaluate Arrhenius' parameters. Hydrolyses were by specific acid-base catalysis. Cocaine showed hydrogen and hydroxyl ion attack on protonated I with 40 and 90% proceeding through the benzoylecgonine route, respectively, as well as hydroxyl ion attack on neutral cocaine, with only 6% proceeding through the benzoylecgonine route. Cocaine is relatively unstable in the neutral pH range with a half-life of 5 hr in buffer at pH 7.25 and 40°. Similar half-lives were observed in fresh dog plasma at 300 and 30 μg/ml, although one study at 0.5 μg/ml indicated a doubling of the rate.