Substituted phenethylamines (SPA) such as methamphetamine (MA) and mephedrone (MD) are destructive to human health and present a significant abuse liability. Since the 1960s illicit use and production of MA has been rampant despite governments attempting to control the drug. MD on the other hand was virtually unknown before the early 2000s, but in recent years use and production of MD has increased at an alarming rate especially in the UK. No FDA approved therapies currently exist to treat SPA addiction. Immunopharmacotherapy i.e. drugs of abuse vaccines (DoAVs) is an attractive option for the treatment of drug addiction because of its low side-effect profile, ease of administration and its long-lived potency. The concept behind drugs of abuse vaccines is that they elicit highly specific humoral immune responses against a target drug compound. Anti-drug antibodies bind to the drug in the periphery, thus preventing the drug from crossing the blood brain barrier. As a result the drug cannot act on receptors in the brain to produce its rewarding, psychological effects. The goal of the proposed research project is to create and test an improved vaccine for treatment of SPA addiction. Previously reported SPA vaccines (specifically MA) have not shown any ability to block self- administration in rat which is an important benchmark for vaccines that hold promise in treating addiction. Furthermore, no report of a working MD vaccine exists in the literature. Increasing epitope density of immunogens is a robust strategy for increasing vaccine performance. This strategy, unexplored in the realm of DoAVs, will be used to create novel SPA vaccines via polymers and dendrimers linked to carrier proteins.
The specific aims for developing SPA vaccines are: (1) Design and synthesize novel MA and MD haptens and test them as vaccines in immunochemical assays and behavioral assays. Mice immunized with the novel hapten-protein conjugates should elicit high titer IgG antibody responses to MA and MD as measured by ELISA and high affinity for drug in radioimmunoassay. Immunized mice should also display a blunting of MA/MD induced hyperlocomotor activity. The novel haptens are hypothesized to be more immunogenic than previously reported haptens since they present the drug-like moiety in its most natural form. (2) Incorporate Aim 1 haptens into novel multihaptenic scaffolds. As vaccines, these scaffolds possess increased epitope density which may boost potency over traditional monovalent vaccines. (3) Evaluate the improved vaccines in rat models. The novel vaccines may hold promise in mitigating the addictive effects of MA/MD in rat self- administration models which are designed to mimic the human condition of drug addiction.
Substituted phenethylamine drugs such as methamphetamine and mephedrone are highly destructive to human health and are known to be addictive. Our goals are to develop urgently needed vaccines against substituted phenethylamines to diminish the detrimental effects of methamphetamine and mephedrone addiction on society.
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| Bremer, Paul T; Hixon, Mark S; Janda, Kim D (2014) Benzoquinones as inhibitors of botulinum neurotoxin serotype A. Bioorg Med Chem 22:3971-81 |
