Cocaine dependency is a long-lasting relapsing illness characterized by cycles of abuse abstinence and reinstatement and antibody-based therapies could be a powerful therapeutic approach. potent cocaine affinity and also elicit antibodies in a higher concentration than the parent structure SNC. Our data suggests that strategic hapten fluorination could be useful for not only improving upon the current cocaine vaccine undergoing clinical trials but it may also be a valuable new approach with application to any of the vaccines being developed for the treatment of drugs of abuse. Cocaine abuse and dependency remains a major medical and public health problem.1 To date no pharmacotherapies have yet to be approved for the treatment of cocaine dependence. However a number of RETRA hydrochloride direct/indirect agonists and antagonists aimed to modulate or disrupt the drug’s effect at RETRA hydrochloride its site of action have been investigated but these have achieved very limited success.2 In view of these limitations interest has turned to strategies that target the drug molecule itself aiming to keep the drug below its effective concentration at its site of action. One such tactic using this approach is termed active vaccination wherein a cocaine vaccine is used to elicit antibodies (Abs) for drug neutralization.2 3 We view active vaccine design to be Rabbit Polyclonal to ITIH1 (Cleaved-Asp672). dependent upon three basic elements: a drug-like hapten immunogenic carrier and adjuvant.3 4 During the past two decades a small but intensive effort has been devoted to exploring cocaine-like haptens to produce cocaine-specific antibodies; yet only one cocaine vaccine termed TA-CD which consists of succinyl norcocaine (SNC Figure 1) coupled to a recombinant cholera toxin B subunit using an aluminum hydroxide gel as adjuvant has reached clinical trials.5 Furthermore this vaccine has offered limited therapeutic efficacy for cocaine abstinence as a result of the high subject-to-subject variability in antibody titers among participants. Thus there is an unmet need to engineer vaccine formulations with improved immunogenicity that will validate vaccination as a therapeutic strategy to treat cocaine abuse and addiction. Figure 1 Structures of cocaine hapten SNC and halogen-containing cocaine haptens. Fluorine substitution is an established tool in bioorganic and medicinal chemistry due to the unique properties of fluorine such as the comparable size of fluorine to hydrogen the superhydrophobicity of fluorocarbons and fluorine’s unique inductive effect and “polar hydrophobicity”.6 Incorporation of fluorine atoms or fluorine-containing substituents is often used to enhance ligand-binding affinities and has recently been found to enhance immune recognition.7 Indeed immune response in part is based on the T cell receptor (TCR) recognition of antigenic molecules bound and presented by major histocompatibility complex (MHC). A weak interaction of TCRs with antigen-MHC RETRA hydrochloride may fail to evoke a significant immune response. There is increasing evidence that rationally modified antigens can boost TCR binding and thereby overcome the poor antigenicity of native antigens. Antigen-fluorination has become one means to enhance TCR affinity without significantly perturbing the composition or structure of the antigen.8 Thus various laboratories have prepared fluorine-modified carbohydrates peptides or glycopeptides and in some cases these variants showed RETRA hydrochloride significant improvement in the immunogenicity of the vaccine.9 An Achilles’ heel seen with vaccines against drugs of abuse has been poor immunogenicity. Herein we detail using cocaine as a drug of abuse platform scaffold how hapten-halogenation can be implemented as a new tool for modulating vaccine potency. The succinyl norcocaine hapten was chosen as a starting structure to examine this hypothesis as modification on this structure could be carefully controlled and immunological consequences readily accounted for. Three fluorine-containing homologues of SNC termed GNF GNCF and GN5F were judiciously chosen and synthesized RETRA hydrochloride (Figure 1) in which the anticipated benzoyl ester dominant epitope was substituted with fluorine(s) or a trifluoromethyl group. Lastly we also prepared a chlorine-containing cocaine hapten GNCl to probe the importance of the halogen atom itself. The synthesis of succinyl norcocaine (SNC) and the corresponding halogenated cocaine haptens is illustrated in Scheme 1. SNC was synthesized using a similar strategy as reported 10 while the synthesis of.