Decoding the Structure of Abuse Potential for New Psychoactive Substances: Structure–Activity Relationships for Abuse-Related Effects of 4-Substituted Methcathinone Analogs

  • S. Stevens NegusEmail author
  • Matthew L. Banks
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 32)


Many cathinone analogs act as substrates or inhibitors at dopamine, norepinephrine, and serotonin transporters (DAT, NET, SERT, respectively). Drug selectivity at DAT vs. SERT is a key determinant of abuse potential for monoamine transporter substrates and inhibitors, such that potency at DAT > SERT is associated with high abuse potential, whereas potency at DAT < SERT is associated with low abuse potential. Quantitative structure–activity relationship (QSAR) studies with a series of 4-substituted methcathinone analogs identified volume of the 4-position substituent on the methcathinone phenyl ring as one structural determinant of both DAT vs. SERT selectivity and abuse-related behavioral effects in an intracranial self-stimulation procedure in rats. Subsequent modeling studies implicated specific amino acids in DAT and SERT that might interact with 4-substituent volume to determine effects produced by this series of cathinone analogs. These studies illustrate use of QSAR analysis to investigate pharmacology of cathinones and function of monoamine transporters.


Dopamine transporter Flephedrone Intracranial self-stimulation Mephedrone Methcathinone Methedrone Microdialysis Serotonin transporter Structure–activity relationship 



This work was supported by R01 DA033930.


  1. 1.
    Baumann MH, Partilla JS, Lehner KR (2013) Psychoactive “bath salts”: not so soothing. Eur J Pharmacol 698:1–5CrossRefGoogle Scholar
  2. 2.
    De Felice LJ, Glennon RA, Negus SS (2014) Synthetic cathinones: chemical phylogeny, physiology, and neuropharmacology. Life Sci 97:20–26CrossRefGoogle Scholar
  3. 3.
    Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL (2015) Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter. Drug Alcohol Depend 147:1–19CrossRefGoogle Scholar
  4. 4.
    Simmler LD, Liechti ME (2016) Interactions of cathinone NPS with human transporters and receptors in transfected cells. Curr Top Behav NeurosciGoogle Scholar
  5. 5.
    Sitte HH, Freissmuth M (2015) Amphetamines, new psychoactive drugs and the monoamine transporter cycle. Trends Pharmacol Sci 36:41–50CrossRefGoogle Scholar
  6. 6.
    Solis E (2016) Electrophysiological actions of synthetic cathinones on monoamine transporters. Curr Top Behav NeurosciGoogle Scholar
  7. 7.
    Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39:32–41CrossRefGoogle Scholar
  8. 8.
    Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, Rothman RB, Roth BL (2003) 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol Pharmacol 63:1223–1229CrossRefGoogle Scholar
  9. 9.
    Suyama JA, Sakloth F, Kolanos R, Glennon RA, Lazenka MF, Negus SS, Banks ML (2016) Abuse-related neurochemical effects of para-substituted methcathinone analogs in rats: microdialysis studies of nucleus accumbens dopamine and serotonin. J Pharmacol Exp Ther 356:182–190CrossRefGoogle Scholar
  10. 10.
    Baumann MH, Clark RD, Rothman RB (2008) Locomotor stimulation produced by 3,4-methylenedioxymethamphetamine (MDMA) is correlated with dialysate levels of serotonin and dopamine in rat brain. Pharmacol Biochem Behav 90:208–217CrossRefGoogle Scholar
  11. 11.
    Aarde SM, Taffe MA (2016) Predicting the abuse liability of entactogen-class new and emerging psychoactive substances via preclinical models of drug self-administration. Curr Top Behav NeurosciGoogle Scholar
  12. 12.
    Carter LP, Griffiths RR (2009) Principles of laboratory assessment of drug abuse liability and implications for clinical development. Drug Alcohol Depend 105(Suppl 1):S14–S25CrossRefGoogle Scholar
  13. 13.
    Olive MF, Watterson L (2016) Reinforcing effects of cathinone NPS in the intravenous drug self-administration paradigm. Curr Top Behav NeurosciGoogle Scholar
  14. 14.
    Wang Z, Woolverton WL (2007) Estimating the relative reinforcing strength of (+/-)-3,4-methylenedioxymethamphetamine (MDMA) and its isomers in rhesus monkeys: comparison to (+)-methamphetamine. Psychopharmacology (Berl) 189:483–488CrossRefGoogle Scholar
  15. 15.
    Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL (2005) Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs. J Pharmacol Exp Ther 313:848–854CrossRefGoogle Scholar
  16. 16.
    Woods JH, Tessel RE (1974) Fenfluramine: amphetamine congener that fails to maintain drug-taking behavior in the rhesus monkey. Science 185:1067–1069CrossRefGoogle Scholar
  17. 17.
    Negus SS, Miller LL (2014) Intracranial self-stimulation to evaluate abuse potential of drugs. Pharmacol Rev 66:869–917CrossRefGoogle Scholar
  18. 18.
    Bauer CT, Banks ML, Blough BE, Negus SS (2013) Use of intracranial self-stimulation to evaluate abuse-related and abuse-limiting effects of monoamine releasers in rats. Br J Pharmacol 168:850–862CrossRefGoogle Scholar
  19. 19.
    Nutt D, King LA, Saulsbury W, Blakemore C (2007) Development of a rational scale to assess the harm of drugs of potential misuse. Lancet 369:1047–1053CrossRefGoogle Scholar
  20. 20.
    Bonano JS, Banks ML, Kolanos R, Sakloth F, Barnier ML, Glennon RA, Cozzi NV, Partilla JS, Baumann MH, Negus SS (2015) Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues. Br J Pharmacol 172:2433–2444CrossRefGoogle Scholar
  21. 21.
    Sakloth F, Kolanos R, Mosier PD, Bonano JS, Banks ML, Partilla JS, Baumann MH, Negus SS, Glennon RA (2015) Steric parameters, molecular modeling and hydropathic interaction analysis of the pharmacology of para-substituted methcathinone analogues. Br J Pharmacol 172:2210–2218CrossRefGoogle Scholar
  22. 22.
    Gregg RA, Baumann MH, Partilla JS, Bonano JS, Vouga A, Tallarida CS, Velvadapu V, Smith GR, Peet MM, Reitz AB, Negus SS, Rawls SM (2015) Stereochemistry of mephedrone neuropharmacology: enantiomer-specific behavioural and neurochemical effects in rats. Br J Pharmacol 172:883–894CrossRefGoogle Scholar
  23. 23.
    Hutsell B, Baumann MH, Partilla J, Banks ML, Verkariya R, Glennon RA, Negus SS (2016) Abuse-related neurochemical and behavioral effects of cathinone and 4-methylcathinone stereoisomers in rats. Eur J Neuropsychopharm 26:288–297CrossRefGoogle Scholar
  24. 24.
    Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, Birkes J, Young R, Glennon RA (2003) In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates. J Pharmacol Exp Ther 307:138–145CrossRefGoogle Scholar
  25. 25.
    Balster RL, Schuster CR (1973) A comparison of d-amphetamine, l-amphetamine, and methamphetamine self-administration in rhesus monkeys. Pharmacol Biochem Behav 1:67–71CrossRefGoogle Scholar
  26. 26.
    Glennon RA, Young R, Hauck AE, McKenney JD (1984) Structure-activity studies on amphetamine analogs using drug discrimination methodology. Pharmacol Biochem Behav 21:895–901CrossRefGoogle Scholar
  27. 27.
    Johanson CE, Schuster CR (1981) A comparison of the behavioral effects of l- and dl-cathinone and d-amphetamine. J Pharmacol Exp Ther 219:355–362PubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyVirginia Commonwealth UniversityRichmondUSA

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