Computational studies of Cathinone And
cathinone derivatives
KIARA LIPSEY
MENTOR: TIFFANI HOLMES, PH.D.
LOUIS STOKES ALLIANCE FOR MINORITY
PARTICIPATION SUMMER RESEARCH PROGRAM
FORT VALLEY STATE UNIVERSITY
JULY 31, 2014
Table of Contents

Khat………………………………………………………………………….1

Cathinone…………………………………………………………………..2

Synthetic Cathinone…………………………………………………….3

Government Regulations……………………………………………..4

Possible Poisonings……………………………………………………..5

Pharmacological Effects……………………………………………….6

Cathinone Derivatives………………………………………………….7

Previous Studies…………………………………………………………..8
 Is a shrub or small tree
Khat
indigenous to East Africa and the
Arabian Peninsula.
 Chewing the khat leaves results in
release of the psychoactive
alkaloids cathinone and cathine.
 In 1975 Cathinone was isolated
from the Khat leaves and
determined to be its principal
psychoactive component.
Cathinone
O
NH2
Fig. 1.
Structure of
cathinone
 Synthetic cathinones are found in
Synthetic
Cathinones
bath salts.
 Bath salts refers to an emerging
family of drugs containing one or
more synthetic chemicals related to
cathinone an amphetamine like
stimulant found naturally in the
Khat plant.
 Mephedrone and methylene
dioxyprovalerone are currently the
predominantly abused synthetic
cathinone.
Bath Salt
Incidents
ABC News Article
 May 2012
 Randy Eugene, a 31-year-old
homeless man, was shot to death after
he had consumed 75 percent of the
flesh on Poppo's face.
 A suspect who had torn off his clothes
was hit by a taxi and then beat the
occupants of the vehicle. It took 15
officers to stop him.
 Behavior was consistent with other
incidents involving bath salts in
Miami.
 Law makers cannot keep pace
Government
Regulations
with bath salt producers
 To control the spread problem ,
the Drug Enforcement Agency
issued a temporary ban in
October on three of the most
common drugs:



mephedrone
methylone
MDPV (methylene dioxyprovalerone)
Possible Poisioning
 After the consumption of bath salts, users have
reported symptoms of poisoning.
 Some symptoms are:







Paranoia and violent behavior
Hallucinations
Delusions
Suicidal thoughts
Panic attacks
Increased heart rate
Increased blood pressure
Pharmacological Effects
Cathinone and its derivatives
exhibit the same effects as
methamphetamines.
Methamphetamines work in the
brain to increase monoamine
(dopamine) levels by:
 Blocking re-uptake of dopamine
 Decreasing expression of
dopamine transporters at cell
surface
 Inhibiting monoamine oxidase
 Increasing activity and
expression of dopamine
synthesizing enzyme tyrosine
hydroxylase.
MDMA (ecstacy)
5-hydroxytryptamine
dopamine
Cathinone Derivatives
R1 = hydrogen, any alkyl group, or incorporation in a cyclic structure
R2 = hydrogen, any alkyl group, or incorporation in a cyclic structure
R3 = hydrogen, or any combination of one or more alkyl, alkoxy, alkylenedioxy, haloalkyl or
halide substituents
R4 = hydrogen or alkyl group
R5 = hydrogen or alkyl group
Previous
Studies
Some studies have
been dedicated to
understanding
biological activity of
some cathinone
derivatives.
Most studies have
been on the
detection of
cathinone and
methylmethcathino
ne in body fluids
Ex: Methylone, butylone, and mephedrone
have been found to inhibit the uptake of
monoamines
Aim
To determine the electronic structure of compounds
not yet synthesized. The electronic structures will
allow for the prediction of the biological activity of
these compounds.
Methods
 Modeled structures using GaussView 5
 Carried out structure optimization and vibrational
frequency calculations using the Gaussian 09
program
 NBO analysis
 Calculated molecular descriptors from output




Dipole Moment
Energy of HOMO
Energy of LUMO
Polarizability
Programs
Gauss View
SSH Secure Shell Client
 Density Functional Theory (DFT)
 widely used method for theoretical
calculations of the structure of atoms,
molecules, surfaces and their interactions.
Methods

Basis Set


set of functions used to describe the
molecular orbitals or density of a
compound.
Example:
B3LYP/6-31G
 B3LYP/6-31G (d)
 B3LYP/6-31G (d,p)
 B3LYP/6-311G (d,p)
 B3LYP/6-311++G (d,p)

Results and Discussion:
Modeled Structures-Compounds of Unknown
Biological Activity
1.225 Å
1.224 Å
4-ethylcathinone
1.225 Å
4-methylcathinone: R1=H R2=H R3 = CH3
R4=H R5=H
cathinone
4-ethylcathinone: R1= H R2=H R3= CH2CH3
R4=H R5=H
3,4-dimethylethcathinone: R1=H R2=CH2CH3
R3= 3,4 CH3 R4=H
1.225 Å
4-methylcathinone
3,4-dimethylethcathinone
Modeled Structures-Compounds of Known
Biological Activity
Methylone
Butylone {2}
Mephedrone
{3}
{1}
Results and Discussion: Calculated Properties
Compounds
E Ta
b
b
E LUMO c
Molecular Weight d
Dipole Moment e
M3 4-methylcathinone
-518.8716
-0.33436
0.09210
163.217
3.46
E3 4-ethylcathinone
-558.1851
-0.33379
0.09181
178.252
3.48
3,4-dimethylethcathinone
-636.8043
-0.20580
-0.05129
205.299
3.34
Methylone 1
-703.1247
-0.31235
0.09634
356.416
3.96
Butylone 2
-742.1589
-0.30527
0.10072
370.442
2.70
Mephedrone 3
-593.6265
-0.32402
0.10040
326.432
2.75
Total molecular energy (hartrees)
Energy of the highest occupied molecular orbital
c Energy of lowest unoccupied molecular orbital
d Molecular weight in amu.
e Total molecular dipole moment in Debye
a
E HOMO
Results
Compounds a
μf
M3 4-methylcathinone
-0.12113
0.21323
0.78677
-0.03441
225.68
-0.567
-0.885
E3 4-ethylcathinone
-0.12099
0.2128
0.7872
-0.0344
240.77
-0.567
-0.885
3,4-dimethylethcathinone
-0.1286
0.0773
0.9227
-0.1069
259.88
-0.558
-0.694
Methylone 1
-0.10801
0.20435
0.79566
-0.02854
256.15
-0.558
-0.689
Butylone 2
-0.10228
0.203
0.79701
-0.02576
278.29
-0.558
-0.702
-0.11181
0.21221
0.78779
-0.02946
249.16
-0.55
-0.697
Mephedrone 3
f
Calculated chemical potential
(negative of the electronegativity)
μ = (ELUMO + EHOMO)/2
g
Chemical hardness
η = (ELUMO – EHOMO)/2
ηg
σh
ωi
h
Chemical softness
σ=1–η
j
i
k
electrophilicity
ω = μ2/2η
N1k
Polarizability O1j
Natural Bond Orbital (NBO) calculated
charge of carbonyl oxygen
NBO calculated charge of nitrogen
in amine group
Results
Descriptors vs. 5-HT IC-50
Polarizability
IC50 = 0.0145P - 3.392
N=3 R2=0.8487
Results
Descriptors vs. Dopamine
Nitrogen Charge
Polarizability
IC50 = -85NC – 58.08
N=3 R2=0.9146
Conclusions
 No significant changes in derivative bond lengths
 Good correlation between polarizability and IC-50 of
5-HT.
 Good correlation between inhibition of dopamine
uptake and nitrogen charge.
Future Work
 Model validation
 Increase the size of the
compound training set.
 More experimental data
from a single source is
needed.
 Identify a test set of
compounds.
References
[1]"Synthetic cathinones." EMCDDA. N.p., n.d. Web. 11 June 2014.
<http://www.emcdda.europa.eu/publications/drug-profiles/synthetic-cathinones>.
[2"Today's Designer Drugs and Recreational Drugs of Abuse." Cayman Chemical New Products. N.p., n.d.
Web. 11 June 2014. <https://www.caymanchem.com/app/template/Article.vm/article/2196>.]
[3] "Overview of Computational Chemistry." Overview of Computational Chemistry. N.p., n.d. Web. 11
June 2014. <http://www.shodor.org/chemviz/overview/ccbasics.html>.
[4] Sharma, S. "Introduction to Density Functional Theory." . N.p., 19 Oct. 2005. Web. 11 June 2014.
<http://perso.neel.cnrs.fr/xavier.blase/dft_Blase.pdf>.
[5] "Drugs and the Nervous System." Drugs and the Nervous System. N.p., n.d. Web. 11 June 2014.
<http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/D/Drugs.html>.
[6] "DrugFacts: Synthetic Cathinones ("Bath Salts")." National Institute on Drug Abuse (NIDA). N.p., n.d.
Web. 11 June 2014. <http://www.drugabuse.gov/publications/drugfacts/synthetic-cathinonesbath-salts>.
[7"'Bath salt' poisonings rise as legislative ban tied up." USATODAY.COM. N.p., n.d. Web. 11 June 2014.
<http://usatoday30.usatoday.com/news/health/story/2012-04-11/synthetic-drugs-bathsalts/54187138/1>.]
References
[8] "Detection and Elimination Profile of Cathinone in Equine after Norephedrine (Propalin®)
Administration Using a Validated Liquid Chromatographyâ tandem Mass Spectrometry Method Springer." Detection and Elimination Profile of Cathinone in Equine after Norephedrine
(Propalin®) Administration Using a Validated Liquid Chromatographyâ tandem Mass
Spectrometry Method - Springer. N.p., 01 Dec. 2013. Web. 15 July 2014.
<http://link.springer.com/article/10.1007%252Fs00216-013-7073-0>.
[9] Writer, By Bahar Gholipour Staff. Yahoo! News. Yahoo!, 15 July 2013. Web. 15 July 2014.
<http://news.yahoo.com/bath-salt-drugs-may-more-addictive-meth-114143987.html>.
[10] "Chemistry in Context: The Cannibalism Causing "Bath Salts"" Antisense Science. N.p., n.d. Web. 15
July 2014. <http://antisensescienceblog.wordpress.com/2013/11/20/chemistry-in-context-thecannibalism-causing-soap/>.
[11] "Tyrosine." Wikipedia. Wikimedia Foundation, 14 July 2014. Web. 15 July 2014.
<http://en.wikipedia.org/wiki/Tyrosine>.
[12] "Thread: Neo-doves Part II." Bluelight RSS. N.p., n.d. Web. 15 July 2014.
<http://www.bluelight.org/vb/threads/349040-Neo-doves-Part-II/page6>.
[13] "Authorities Seize Bath Salts in Austin Drug Bust." - MyFoxAustin.com. N.p., n.d. Web. 15 July 2014.
<http://www.myfoxaustin.com/story/19131551/authorities-seize-bath-salts-in-austin-drugbust>.
[14] "Video: The Hazards of 'Bath Salts'" - Editor's Notes. N.p., n.d. Web. 15 July 2014.
<http://www.policemag.com/blog/editors-notes/story/2012/06/the-hazards-of-bathsalts.aspx>.
[15] "New Drug Snapchat Taking down the Aussies." RSS. N.p., n.d. Web. 15 July 2014.
<http://www.martinmobileap.com/mmap-blog/2014/6/16/new-drug-snapchat-taking-downthe-aussies>.
[16] "DEA Assigns Temporary Placement of 10 Synthetic Cathinones Into Schedule I." American
Substance Abuse Professionals Inc. N.p., n.d. Web. 15 July 2014.
<https://go2asap.com/node/267>.
[17] "Police Go Soft on Khat: Officers Told to Respect 'culture and History' of Anyone Caught Chewing
the Drug after Ban Comes into Force !!!" Defender of FaithGuardian of Truth. N.p., n.d. Web. 15
July 2014. <http://cpnagasaki.wordpress.com/2014/06/23/police-go-soft-on-khat-officers-toldto-respect-culture-and-history-of-anyone-caught-chewing-the-drug-after-ban-comes-intoforce/>.
[18] "News: Engineering." Nobel Prize in Chemistry: Imperial Scientists Give Their Reaction. N.p., n.d.
Web. 15 July 2014.
References
[19]"Face-Eating Cannibal Attack May Be Latest in String of 'Bath Salts' Incidents." ABC
News. ABC News Network, n.d. Web. 16 July 2014.
Acknowledgements
 Fort Valley State University’s Department of
Chemistry
 FVSU’s Peach State Louis Stokes Alliance for
Minority Participation Program
 Dr. T.M.Holmes
 Dr. Dwayne Daniels
 Dr. Robin Bright