Abuse of the class of illicit drugs known as cathinones or bath salts is a dangerous and growing worldwide problem. This project will focus on two medically important cathinones, MDPV and alpha-PVP. These two designer psychostimulant drugs were chosen because they are most often associated with human abuse and toxicity. Through their actions as dual reuptake inhibitors of norepinephrine and dopamine they elicit CNS effects, cardiovascular (CV) hypertension and tachycardia, agitation, seizures, violent behaviors, and death. Scientific evidence suggests the (S)-isomers of MDVP and alpha-PVP are the most potent stereoisomers for producing CNS psychoactive stimulant effects. Thus, we hypothesize that treatment of racemic MDPV or alpha-PVP toxicity with a high affinity monoclonal antibody (mAb) against (S)-MDPV and (S)-alpha-PVP can protect abusers from harmful psychoactive stimulant effects. We will also determine which isomer(s) cause CV toxicity, and generate mAb medications against the most active isomeric form.
The specific aims i nclude 1) development of important endpoints for assessing anti-cathinone mAb therapeutic efficacy in male and female rats, 2) synthesis of novel cathinone-like antigenic haptens for use in making a high affinity anti-MDPV and alpha-PVP mAb, 3) testing of the ability of these new therapies to reduce MDPV- and alpha-PVP-induced adverse effects in male and female rats. Upon successful completion of these studies we will have determined the relative medical importance of cathinone stereoisomers, and developed the first specific medication for treating cathinone abuse.

Public Health Relevance

This research aims to develop highly specific medical therapies for the treatment of abuse of two of the most medically dangerous cathinones or 'bath salts'. Through innovative integration of experimental therapeutics, chemistry, immunology and behavioral science, novel monoclonal antibody medicines will be created to treat overdose and protect patients from the harmful effects of relapse to cathinone abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA039195-02
Application #
9043007
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rapaka, Rao
Project Start
2015-04-15
Project End
2019-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Pharmacology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
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Fantegrossi, William E; Wilson, Catheryn D; Berquist, Michael D (2018) Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin, and glutamate systems. Drug Metab Rev 50:65-73
Hambuchen, Michael D; Hendrickson, Howard P; Gunnell, Melinda G et al. (2017) The pharmacokinetics of racemic MDPV and its (R) and (S) enantiomers in female and male rats. Drug Alcohol Depend 179:347-354
Hambuchen, Michael D; Hendrickson, Howard P; Owens, S Michael (2017) Chiral determination of 3,4-methylenedioxypyrovalerone enantiomers in rat serum. Anal Methods 9:609-617
Gannon, Brenda M; Russell, Lauren N; Modi, Meet S et al. (2017) Effects of orally self-administered bath salt constituent 3,4-methylenedioxypyrovalerone (MDPV) in mice. Drug Alcohol Depend 179:408-415
Gannon, Brenda M; Fantegrossi, William E (2016) Cocaine-Like Discriminative Stimulus Effects of Mephedrone and Naphyrone in Mice. J Drug Alcohol Res 5: