Design, synthesis and biological evaluation of a bi-specific vaccine against α-pyrrolidinovalerophenone (α-PVP) and 3,4-methylenedioxypyrovalerone (MDPV) in rats.

α-PVP (α-pyrrolidinovalerophenone) and MDPV (3,4-methylenedioxypyrovalerone) are potent abused stimulants that are members of the synthetic cathinone class of drugs. Although these drugs are taken with recreational intent, high doses can lead to unintended adverse effects including agitation, cardiovascular effects, sympathomimetic syndromes, hallucinations, and psychoses. One possible treatment is the use of a vaccine to block or attenuate adverse medical effects. These studies report the preparation of a vaccine that generates high affinity antibodies specific for both drugs and the pharmacological testing of this vaccine in male rats. Alkylation of a hydroxy-α-PVP analog with an appropriate thiol-bearing linker afforded the hapten. When hapten-conjugated carrier protein was mixed with adjuvant, the resulting vaccine stimulated production of antibodies in male Sprague Dawley rats that were found to significantly reduce α-PVP- and MDPV-induced hyperlocomotion as well as to significantly reduce the concentrations of MDPV drugs in critical organs. The novel vaccine produced high affinity antibodies against MDPV, (R)-MDPV, (S)-MDPV, and α-PVP. Cross-reactivity testing against nine structurally similar cathinones showed very limited binding, and no binding to off-target endogenous and exogenous compounds. Antibodies generated by this bi-specific vaccine also significantly shortened the duration of locomotor activity induced by both drugs up to a dose of 5.6 mg/kg in male rats.

Interview with Frank Ivy Carroll.

Frank Ivy Carroll received his BS degree in chemistry from Auburn University (AL, USA) in 1957 and was awarded the PhD in chemistry by the University of North Carolina at Chapel Hill (NC, USA) in 1961. He joined the research staff of the Research Triangle Institute (NC, USA) as a Research Chemist and rose steadily to the position of Vice President of the Chemistry and Life Sciences Group, a position he held from 1996-2001. Dr Carroll also served as Director of the Center for Organic and Medicinal Chemistry from 1975-2007. He is presently Distinguished Fellow for Medicinal Chemistry. Dr Carroll has varied research interests, but since 1990, a major thrust of his research efforts has involved development of pharmacotherapies for substance abuse (cocaine, nicotine, methamphetamine, opioids and ethanol) and other CNS disorders. Dr Carroll has published 468 peer-reviewed articles, 33 book chapters and 46 patents and has received numerous awards for his research accomplishments; the most recent are: the 2010 North Carolina Award for Science; the 2010 National Institute on Drug Abuse Public Service Award for Significant Achievement; and the 2012 Alfred Burger Award in Medicinal Chemistry from the American Chemical Society. In 2007, he was inducted into the American Chemical Society Medicinal Chemistry Hall of Fame. Interview conducted by Hannah Coaker, Assistant Commissioning Editor.

Bupropion and its main metabolite reverse nicotine chronic tolerance in the mouse.

INTRODUCTION: Although the antidepressant bupropion is prescribed to aid in smoking cessation, little is known concerning its mechanisms of action in this regard. One factor that might influence quit success is nicotine tolerance, which could promote high levels of nicotine intake in order to maintain nicotine's subjective effects (thereby making attempts to reduce smoking more difficult). METHODS: To explore whether bupropion and its active hydroxymetabolite modulate nicotine tolerance, mice were injected for 14 days with saline or nicotine. On Day 14, animals received saline, (2S,3S)-hydroxybupropion, or bupropion at different doses. On Day 15, mice were assayed on test day for nicotine-induced analgesia and hypothermia. RESULTS: Animals chronically injected with saline + nicotine developed tolerance to nicotine's effects in both assays. Administration of bupropion and (2S,3S)-hydroxybupropion dose-dependently reversed chronic nicotine tolerance. CONCLUSIONS: These results indicate that bupropion's ability to promote smoking cessation may be partly due to its attenuation of nicotine tolerance since both measured responses of nicotine (antinociception and hypothermia) are mediated to a large extent by neuronal α4ß2* nicotine receptors.

Effect of the selective kappa-opioid receptor antagonist JDTic on nicotine antinociception, reward, and withdrawal in the mouse.

RATIONALE: Several lines of evidence support a role for the endogenous opioid system in mediating behaviors associated with drug dependence. Specifically, recent findings suggest that the kappa-opioid receptor (KOR) may play a role in aspects of nicotine dependence, which contribute to relapse and continued tobacco smoking. OBJECTIVE: The objective of this study is to determine the involvement of the KOR in the initial behavioral responses of nicotine, nicotine reward, and nicotine withdrawal using the highly selective KOR antagonist JDTic. JDTic doses of 1, 4, 8, or 16 mg/kg were administered subcutaneously (s.c.) 18 h prior to nicotine treatment. RESULTS: JDTic dose-dependently blocked acute nicotine-induced antinociception in the tail-flick but not the hot-plate test and did not significantly attenuate morphine's antinociceptive effect in either the tail-flick or hot-plate test. Furthermore, JDTic (8 and 16 mg/kg, s.c.) failed to block the expression of nicotine reward as measured by the conditioned place preference model. In contrast, JDTic and the KOR antagonist norBNI attenuated the expression of both the physical (somatic signs and hyperalgesia) and affective (anxiety-related behavior and conditioned place aversion) nicotine withdrawal signs. CONCLUSIONS: Our findings clearly show that the KOR is involved in mediating the withdrawal aspects of nicotine dependence. The results from this study suggest that blockade of the KOR by selective KOR antagonists may be useful smoking cessation pharmacotherapies.