112574-76-2Relevant academic research and scientific papers
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 (1999)
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.
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.
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.
