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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others ReferencesBaumann MH, Partilla JS, Lehner KR (2013) Psychoactive “bath salts”: not so soothing. Eur J Pharmacol 698:1–5
De Felice LJ, Glennon RA, Negus SS (2014) Synthetic cathinones: chemical phylogeny, physiology, and neuropharmacology. Life Sci 97:20–26
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 147:1–19
Simmler LD, Liechti ME (2016) Interactions of cathinone NPS with human transporters and receptors in transfected cells. Curr Top Behav Neurosci
Sitte HH, Freissmuth M (2015) Amphetamines, new psychoactive drugs and the monoamine transporter cycle. Trends Pharmacol Sci 36:41–50
Solis E (2016) Electrophysiological actions of synthetic cathinones on monoamine transporters. Curr Top Behav Neurosci
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 39:32–41
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 63:1223–1229
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 356:182–190
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 90:208–217
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 Neurosci
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–S25
Olive MF, Watterson L (2016) Reinforcing effects of cathinone NPS in the intravenous drug self-administration paradigm. Curr Top Behav Neurosci
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) 189:483–488
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 313:848–854
Woods JH, Tessel RE (1974) Fenfluramine: amphetamine congener that fails to maintain drug-taking behavior in the rhesus monkey. Science 185:1067–1069
Negus SS, Miller LL (2014) Intracranial self-stimulation to evaluate abuse potential of drugs. Pharmacol Rev 66:869–917
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 168:850–862
Nutt D, King LA, Saulsbury W, Blakemore C (2007) Development of a rational scale to assess the harm of drugs of potential misuse. Lancet 369:1047–1053
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 172:2433–2444
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 172:2210–2218
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 172:883–894
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 26:288–297
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 307:138–145
Balster RL, Schuster CR (1973) A comparison of d-amphetamine, l-amphetamine, and methamphetamine self-administration in rhesus monkeys. Pharmacol Biochem Behav 1:67–71
Glennon RA, Young R, Hauck AE, McKenney JD (1984) Structure-activity studies on amphetamine analogs using drug discrimination methodology. Pharmacol Biochem Behav 21:895–901
Johanson CE, Schuster CR (1981) A comparison of the behavioral effects of l- and dl-cathinone and d-amphetamine. J Pharmacol Exp Ther 219:355–362
This work was supported by R01 DA033930.
Author information Authors and AffiliationsDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
S. Stevens Negus & Matthew L. Banks
Correspondence to S. Stevens Negus .
Editor information Editors and AffiliationsDesigner Drug Research Unit (DDRU), National Institute on Drug Abuse, Baltimore, MD, USA
Michael H. Baumann
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA
Richard A. Glennon
RTI International, Research Triangle Park, NC, USA
Jenny L. Wiley
© 2016 Springer International Publishing Switzerland
About this chapter Cite this chapterNegus, S.S., Banks, M.L. (2016). Decoding the Structure of Abuse Potential for New Psychoactive Substances: Structure–Activity Relationships for Abuse-Related Effects of 4-Substituted Methcathinone Analogs. In: Baumann, M.H., Glennon, R.A., Wiley, J.L. (eds) Neuropharmacology of New Psychoactive Substances (NPS). Current Topics in Behavioral Neurosciences, vol 32. Springer, Cham. https://doi.org/10.1007/7854_2016_18
Download citationDOI: https://doi.org/10.1007/7854_2016_18
Published: 01 October 2016
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-52442-9
Online ISBN: 978-3-319-52444-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)
RetroSearch is an open source project built by @garambo | Open a GitHub Issue
Search and Browse the WWW like it's 1997 | Search results from DuckDuckGo
HTML:
3.2
| Encoding:
UTF-8
| Version:
0.7.4