PMID- 23583454
OWN - NLM
STAT- MEDLINE
DCOM- 20130809
LR  - 20221207
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 85
IP  - 12
DP  - 2013 Jun 15
TI  - Substituted methcathinones differ in transporter and receptor interactions.
PG  - 1803-15
LID - S0006-2952(13)00228-1 [pii]
LID - 10.1016/j.bcp.2013.04.004 [doi]
AB  - The use of synthetic methcathinones, components of "bath salts," is a world-wide 
      health concern. These compounds, structurally similar to methamphetamine (METH) 
      and 3,4-methylendioxymethamphetamine (MDMA), cause tachycardia, hallucinations 
      and psychosis. We hypothesized that these potentially neurotoxic and abused 
      compounds display differences in their transporter and receptor interactions as 
      compared to amphetamine counterparts. 3,4-Methylenedioxypyrovalerone and 
      naphyrone had high affinity for radioligand binding sites on recombinant human 
      dopamine (hDAT), serotonin (hSERT) and norepinephrine (hNET) transporters, 
      potently inhibited [(3)H]neurotransmitter uptake, and, like cocaine, did not induce 
      transporter-mediated release. Butylone was a lower affinity uptake inhibitor. In 
      contrast, 4-fluoromethcathinone, mephedrone and methylone had higher inhibitory 
      potency at uptake compared to binding and generally induced release of preloaded 
      [(3)H]neurotransmitter from hDAT, hSERT and hNET (highest potency at hNET), and 
      thus are transporter substrates, similar to METH and MDMA. At hNET, 
      4-fluoromethcathinone was a more efficacious releaser than METH. These 
      substituted methcathinones had low uptake inhibitory potency and low efficacy at 
      inducing release via human vesicular monoamine transporters (hVMAT2). These 
      compounds were low potency (1) h5-HT(1A) receptor partial agonists, (2) h5-HT(2A) 
      receptor antagonists, (3) weak h5-HT(2C) receptor antagonists. This is the first 
      report on aspects of substituted methcathinone efficacies at serotonin (5-HT) 
      receptors and in superfusion release assays. Additionally, the drugs had no 
      affinity for dopamine receptors, and high-nanomolar to mid-micromolar affinity 
      for hSigma1 receptors. Thus, direct interactions with hVMAT2 and serotonin, 
      dopamine, and hSigma1 receptors may not explain psychoactive effects. The primary 
      mechanisms of action may be as inhibitors or substrates of DAT, SERT and NET.
CI  - Published by Elsevier Inc.
FAU - Eshleman, Amy J
AU  - Eshleman AJ
AD  - Research Service, Veterans Affairs Medical Center, Portland, OR, USA. 
      eshleman@ohsu.edu
FAU - Wolfrum, Katherine M
AU  - Wolfrum KM
FAU - Hatfield, Meagan G
AU  - Hatfield MG
FAU - Johnson, Robert A
AU  - Johnson RA
FAU - Murphy, Kevin V
AU  - Murphy KV
FAU - Janowsky, Aaron
AU  - Janowsky A
LA  - eng
GR  - P50 DA018165/DA/NIDA NIH HHS/United States
GR  - Y01 DA005007/DA/NIDA NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20130410
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (1-naphthalen-2-yl-2-pyrrolidin-1-ylpentan-1-one)
RN  - 0 (Benzodioxoles)
RN  - 0 (Designer Drugs)
RN  - 0 (Dopamine Plasma Membrane Transport Proteins)
RN  - 0 (Norepinephrine Plasma Membrane Transport Proteins)
RN  - 0 (Pentanones)
RN  - 0 (Propiophenones)
RN  - 0 (Pyrrolidines)
RN  - 0 (Receptors, Serotonin)
RN  - 0 (SLC18A2 protein, human)
RN  - 0 (SLC6A2 protein, human)
RN  - 0 (Serotonin Plasma Membrane Transport Proteins)
RN  - 0 (Symporters)
RN  - 0 (Vesicular Monoamine Transport Proteins)
RN  - 386QA522QG (monomethylpropion)
RN  - 44RAL3456C (Methamphetamine)
RN  - 8BA8T27317 (mephedrone)
RN  - 0 (Synthetic Cathinone)
SB  - IM
MH  - Benzodioxoles/chemistry/metabolism
MH  - Designer Drugs/chemistry/*metabolism
MH  - Dopamine Plasma Membrane Transport Proteins/metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Methamphetamine/analogs & derivatives/chemistry/metabolism
MH  - Norepinephrine Plasma Membrane Transport Proteins/metabolism
MH  - Pentanones/chemistry/metabolism
MH  - Propiophenones/chemistry/*metabolism
MH  - Protein Binding/drug effects/physiology
MH  - Pyrrolidines/chemistry/metabolism
MH  - Receptors, Serotonin/*metabolism
MH  - Serotonin Plasma Membrane Transport Proteins/metabolism
MH  - Symporters/*metabolism
MH  - Vesicular Monoamine Transport Proteins/*metabolism
MH  - Synthetic Cathinone
PMC - PMC3692398
MID - NIHMS466830
COIS- The authors have no actual or potential conflicts of interest.
EDAT- 2013/04/16 06:00
MHDA- 2013/08/10 06:00
PMCR- 2014/06/15
CRDT- 2013/04/16 06:00
PHST- 2013/02/08 00:00 [received]
PHST- 2013/04/03 00:00 [revised]
PHST- 2013/04/03 00:00 [accepted]
PHST- 2013/04/16 06:00 [entrez]
PHST- 2013/04/16 06:00 [pubmed]
PHST- 2013/08/10 06:00 [medline]
PHST- 2014/06/15 00:00 [pmc-release]
AID - S0006-2952(13)00228-1 [pii]
AID - 10.1016/j.bcp.2013.04.004 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2013 Jun 15;85(12):1803-15. doi: 10.1016/j.bcp.2013.04.004. 
      Epub 2013 Apr 10.