Vaccines against drug abuse: morphine-hapten design and synthesis

Drugs of abuse are small molecules that typically do not induce an antibody response following injection or inhalation. To induce antibodies against small molecules, structural surrogates of the molecules, which were named “haptens”, must be coupled to immunogenic proteins, called “carriers”. These structural surrogates are typically drug-linker adducts, in which the linker has a terminal functional group that forms a covalent bond with the carrier. The efficacy of these conjugate vaccines depends on several factors including hapten design, coupling strategy, hapten density, carrier protein selection, and vaccine adjuvant.

We designed N-substituted morphine compounds and for this purpose the normorphine-derivatives were required. (Dihydro)morphine, (dihydro)codeine, oxymorphone and oxycodone were N-demethylated with a-chloroethyl chloroformate to obtain the desired nor-compounds.

These six nor-molecules were reacted with ethyl acrylate and ethyl bromoacetate. After the synthesis of the specific esters we hydrolyzed them to receive the N-carboxymethyl- and N-carboxyethyl-normorphine derivatives. The next step was the coupling phase with glycine ethyl ester, but the reactions didn’t work or the work-up process was not accomplishable. As an alternative route the normorphine-compounds were reacted with N-chloroacetyl glycine ethyl ester.

R₁R₂NH + Cl-CH₂CONH-CH₂COOEt ---> R₁R₂N-CH₂CONH-CH₂COOEt --- hydr. ---> R₁R₂N-CH₂CONH-CH₂COOH

After column chromatography purification the structures of the new compounds were elucidated by NMR and mass spectroscopy. These products were hydrolyzed in alkaline media and after the work-up process all of the derivatives contained the free carboxylic group of the glycine sidechain, confirmed by NMR measurements. All of the glycine ester and the glycine carboxylic acid derivatives are under biological tests.