Synthesis of an Immunogenic Template for the Generation of Catalytic Antibodies for (−)-Cocaine Hydrolysis

Berkman, Clifford E.; Underiner, Gail E.; Cashman, John R.

doi:10.1021/jo960522q

Cited by 17 publications

(19 citation statements)

References 9 publications

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“…That endo-face addition predominated in the reaction products observed was somewhat surprising in view of the fact that addition of Grignard reagents has been shown to give mainly addition to the exo face, and for tropanes, the exo face can be regarded as the less stereochemically hindered site of approach. To test the possiblity that the N-8 tertiary amine moiety was controlling the product stereochemistry, the N-8 carbobenzyloxy-protected anhydronorecgonine methyl ester was prepared by treating norcocaine with concentrated HCl followed by carbobenzyloxy chloride as described previously (25). The carbamate-protected N-8 amino group possessed significantly different basicity compared to the amino group of anhydroecgonine methyl ester.…”

Section: Resultsmentioning

confidence: 99%

Cocaine Benzoyl Thioester: Synthesis, Kinetics of Base Hydrolysis, and Application to the Assay of Cocaine Esterases

Cashman

Berkman

Underiner

et al. 1998

Chem. Res. Toxicol.

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The synthesis and characterization of diastereomers of cocaine benzoyl thioester is described. Allococaine benzoyl thioester and allopseudococaine benzoyl thioester were synthesized by the conjugate addition of p-methoxytolyl thiol to ecgonine methyl ester followed by debenzylation and benzoylation. The absolute structure of the hydrochloride salt of the major ecgonine p-methoxytolyl sulfide formed was determined by single-crystal diffraction analysis and used to establish the addition geometry. When placed in aqueous solution, the cocaine benzoyl thioester diastereomers hydrolyzed to give thioecgonine methyl ester. The rate of cocaine benzoyl thioester hydrolysis was carefully investigated spectrophotometrically by using the Ellman reagent. At neutral pH, the hydrolysis of the diastereomers was found to proceed at detectable rates. Upon increasing pH, the rate of hydrolysis of cocaine benzoyl thioester diastereomers was increased and the reaction was catalyzed by basic buffer species. In addition to defining the kinetics of hydrolysis in aqueous solution, cocaine benzoyl thioester was utilized as a highly efficient method to monitor the activity of cholinesterases and pig liver esterase. Use of cocaine benzoyl thioester represents a rapid and sensitive way to screen for cocaine esterase activity.

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Section: Resultsmentioning

confidence: 99%

Cocaine Benzoyl Thioester: Synthesis, Kinetics of Base Hydrolysis, and Application to the Assay of Cocaine Esterases

Cashman

Berkman

Underiner

et al. 1998

Chem. Res. Toxicol.

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“…The cocaine molecule has several positions where linkers may be conveniently attached: the nitrogen, the methyl ester, and the benzoic acid ester. In the 1990s, there was interest in generating catalytic antibodies against cocaine which would hydrolyze the benzoic acid moiety of cocaine to give the inactive metabolite ecgonine methyl ester [Landry et al 1993;Chandrakumar et al 1993;Basmadjian et al 1995;Yang et al 1996;Berkman et al 1996]. Landry and coworkers showed that such catalytic antibodies were effective against cocaine's effects in rats [Mets et al 1998;Deng et al 2002].…”

Section: Cocaine Vaccinesmentioning

confidence: 99%

Vaccines against drugs of abuse: where are we now?

Kinsey

2014

Therapeutic Advances in Vaccines

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Drug addiction is a serious problem worldwide. One therapy being investigated is vaccines against drugs of abuse. The antibodies elicited against the drug can take up the drug and prevent it from reaching the reward centers in the brain. Few such vaccines have entered clinical trials, but research is going on apace. Many studies are very promising and more clinical trials should be coming out in the near future.

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“…These metabolites have little if any pharmacological activity. There was considerable interest in the 1990's in the creation of catalytic antibodies which would act along the lines of HBC, and papers were published by Chandrakumar (21), Landry (22), Basmadjian (23) and Berkman (24). Clever chemistry was used to create haptens known as transition state analogs in order to mimic the intermediate, usually unstable chemical structures that lead to the hydrolysis reaction, so that the antibodies produced would act as enzymes to catalyze the release of the benzoyl group from cocaine.…”

Section: Anti-cocaine Vaccines Leading To Catalytic Antibodiesmentioning

confidence: 99%

Anti-cocaine vaccine development

Kinsey¹,

Kosten²,

Orson³

2010

Expert Review of Vaccines

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Cocaine abuse is an ongoing and serious problem which has lead to the growth of a brutal criminal enterprise, particularly in the Americas and Europe. At present, there are no effective pharmacological agents available to treat the addiction by blocking cocaine or reversing its effects. In order to help motivated addicts conquer their addiction, vaccines against cocaine are being developed, and one has progressed to clinical trials. This review will discuss the concept of anti-drug vaccines in general, the successes and limitations of the various anti-cocaine vaccine approaches, the results of the clinical trials with an anti-cocaine vaccine, and some new vaccine-mediated approaches to combat cocaine addiction. KeywordsSubstance Abuse; Vaccination; Cocaine; Immunotherapy HistoryCocaine is one of the oldest known drugs. The leaves of the coca plant have been chewed by the indigenous peoples of South America for thousands of years to increase stamina for high altitude work and to afford feelings of well-being. In 1859, the active ingredient in coca was isolated and named cocaine, and it was considered a rather benign drug until the beginning of the 20 th century, when the negative aspects of its use became widely recognized (1). The sale and distribution of opium, coca leaves, and their derivatives was restricted in the United States under the 1914 Harrison Narcotics Tax Act to the practice of medicine, dentistry, and veterinary medicine. However, the law was not strictly enforced for cocaine, and there was open use of the drug for a number of years, although this was generally limited to the minority and low income urban populations, artists, and musicians (2). The addictive properties of cocaine were again gradually recognized, but in spite of this and increased efforts to enforce drug laws, the use of cocaine, particularly the smoked free base form known as crack, exploded during the 1970's and 80's. There is some light on the horizon, however, as data gathered by SAMSHA, the Substance Abuse and Mental Health Services Administration of the US Department of Health and Human Services shows that admissions to substance abuse treatment for cocaine decreased from 1995 to 2005, and the age of those admitted went up substantially (3). Even though there was a decrease in admissions among African-Americans, there was an increase Anti-drug VaccinesIt has been known and studied for at least 50 years that small molecules (haptens) will not usually elicit an immune response unless they are covalently attached to an immunogenic protein (6,7). This results in the body's tolerance for most medications and chemical exposures without significant harmful immune reactions. Allergic reactions to medicines like penicillin occur when the immune system recognizes the chemical or its metabolic products after they have been bound to native proteins, allowing for antigen presentation and initiation of the immune response (8). Therefore, to produce an anti-drug vaccine, the hapten is covalently attached to a foreign carrier prote...

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Synthesis of an Immunogenic Template for the Generation of Catalytic Antibodies for (−)-Cocaine Hydrolysis

Cited by 17 publications

References 9 publications

Cocaine Benzoyl Thioester: Synthesis, Kinetics of Base Hydrolysis, and Application to the Assay of Cocaine Esterases

Cocaine Benzoyl Thioester: Synthesis, Kinetics of Base Hydrolysis, and Application to the Assay of Cocaine Esterases

Vaccines against drugs of abuse: where are we now?

Anti-cocaine vaccine development

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