The aim of this proposal is to discover the underlying basis for the devastating effect of new drugs entering the illicit market. What makes the project especially interesting is that these new drugs are structurally related to the well-known drugs, amphetamine and methamphetamine (AMPH and METH). One of the new drugs is cathinone (khat), a naturally occurring -keto derivative of AMPH~ another is methcathinone (MCAT), an analogous derivative of METH. The infamous and contemporary drug, bath salts, now penetrating our society with cruel effect, is composed of two additional derivatives of the basic -keto amphetamine structure, mephedrone (MEPH) and MDPV. To give a forerunner of a recent discovery, we believe that one of the bath salts ingredients (MEPH) is METH-like, i.e., a dopamine releaser via the human dopamine transporter (hDAT), while the other component (MDPV) is cocaine-like, acting as an hDAT blocker. This horrific combination may well account for the devastating effects reported by hospitals for bath salts victims. New drugs will continue t appear on the market, and it is difficult for the Food and Drug Administration to keep up with illegal variants and novel abuses. One of our objectives, therefore, is to codify structural varians of the -keto amphetamines (synthetic cathinones) that will predict their effects and speed societal and scientific responses to compounds as they appear on the street, and even before they appear. We approach this research from three complementary directions. First is our collaboration with a medicinal chemist, who will synthesize variations of the lead cathinones, to help understand important moieties and variations behind drug actions, and presently unavailable optical isomers to help uncover underlying mechanisms. Street drugs are invariably racemates, which we also study, but it is of interest to study right- and left-handed versions of synthetic cathinones to see which is more active and study possible positive or negative synergy between the two forms. Second, we will study the direct effect of street drugs and synthesized variants on the dopamine transporter in cell membranes under voltage and chemical control. How do METH and MCAT differ in their ability to stimulate transporters? Which of the synthetic cathinones are stimulants (producing electrical signals indicative of DA release) and which are blockers (producing inhibitory signals)? Because the drugs in question have overlapping effects on the dopaminergic and serotonergic systems, we will also study the biophysical effects of synthetic cathinones on the human serotonin transporter. Finally, we have teamed up with a neuropharmacologist who will measure the release of dopamine and serotonin in regions of the rodent brain associated with drug abuse and in response to specific synthetic cathinones or combination of drugs, as in bath salts. The abuse potential of test drugs will also be measured in self-administration protocols in rodents. We think this combined approach of medicinal chemistry, membrane biophysics, and neurochemistry and behavior has the potential to impact important problems in drug abuse to the benefit of basic science research and society in the 21st century.

Public Health Relevance

Synthetic cathinones, also known colloquially as 'Bath Salts,' have been identified by the Drug Enforcement Agency as an emerging domestic drug abuse threat. This project will investigate molecular mechanisms and abuse-related pharmacology of cathinone and its synthetic derivatives using multidisciplinary tools of medicinal chemistry, membrane biophysics, and whole-animal neurochemistry and behavior. Results will clarify the threat and provide a basis for developing appropriate responses and treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
4R01DA033930-05
Application #
9100698
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rapaka, Rao
Project Start
2012-04-15
Project End
2017-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Physiology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Suyama, J A; Banks, M L; Negus, S S (2018) Effects of repeated treatment with methcathinone, mephedrone, and fenfluramine on intracranial self-stimulation in rats. Psychopharmacology (Berl) :
Johnson, Amy R; Banks, Matthew L; Selley, Dana E et al. (2018) Amphetamine maintenance differentially modulates effects of cocaine, methylenedioxypyrovalerone (MDPV), and methamphetamine on intracranial self-stimulation and nucleus accumbens dopamine in rats. Neuropsychopharmacology 43:1753-1762
Moerke, Megan J; Ananthan, Subramaniam; Banks, Matthew L et al. (2018) Interactions between Cocaine and the Putative Allosteric Dopamine Transporter Ligand SRI-31142. J Pharmacol Exp Ther 367:222-233
Battisti, Umberto M; Sitta, Ramsey; Harris, Alan et al. (2018) Effects of N-Alkyl-4-Methylamphetamine Optical Isomers on Plasma Membrane Monoamine Transporters and Abuse-Related Behavior. ACS Chem Neurosci 9:1829-1839
Sakloth, Farhana; Negus, S Stevens (2018) Naltrexone maintenance fails to alter amphetamine effects on intracranial self-stimulation in rats. Exp Clin Psychopharmacol 26:195-204
Steele, Tyler W E; Eltit, Jose M (2018) Using Ca2+-channel biosensors to profile amphetamines and cathinones at monoamine transporters: electro-engineering cells to detect potential new psychoactive substances. Psychopharmacology (Berl) :
Smith, Douglas A; Blough, Bruce E; Banks, Matthew L (2017) Cocaine-like discriminative stimulus effects of amphetamine, cathinone, methamphetamine, and their 3,4-methylenedioxy analogs in male rhesus monkeys. Psychopharmacology (Berl) 234:117-127
Negus, S Stevens; Banks, Matthew L (2017) Decoding the Structure of Abuse Potential for New Psychoactive Substances: Structure-Activity Relationships for Abuse-Related Effects of 4-Substituted Methcathinone Analogs. Curr Top Behav Neurosci 32:119-131
Glennon, Richard A (2017) The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The ""Phenylalkylaminome"" with a Focus on Selected Drugs of Abuse. J Med Chem 60:2605-2628
Smith, Douglas A; Negus, S Stevens; Poklis, Justin L et al. (2017) Cocaine-like discriminative stimulus effects of alpha-pyrrolidinovalerophenone, methcathinone and their 3,4-methylenedioxy or 4-methyl analogs in rhesus monkeys. Addict Biol 22:1169-1178

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