KIARA LIPSEY MENTOR: TIFFANI HOLMES, PH.D.

LOUIS STOKES ALLIANCE FOR MINORITY PARTICIPATION SUMMER RESEARCH PROGRAM

FORT VALLEY STATE UNIVERSITY JULY 31, 2014

Computational studies of Cathinone And cathinone derivatives

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

Khat

Is a shrub or small tree 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

NH2

O

Fig. 1. Structure of cathinone

Synthetic Cathinones

Synthetic cathinones are found in 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.

Government Regulations

Law makers cannot keep pace 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 dopamineDecreasing expression of dopamine transporters at cell surfaceInhibiting monoamine oxidaseIncreasing 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 substituentsR4 = hydrogen or alkyl group

R5 = hydrogen or alkyl group

Previous StudiesSome studies have been dedicated to understanding biological activity of some cathinone derivatives.

Most studies have been on the detection of cathinone and methylmethcathinone in body fluids

Ex: Methylone, butylone, and mephedronehave 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.

Modeled structures using GaussView 5Carried out structure optimization and

vibrational frequency calculations using the Gaussian 09 program

NBO analysisCalculated molecular descriptors from output

Dipole Moment Energy of HOMO Energy of LUMO Polarizability

Methods

Gauss ViewGauss View SSH Secure Shell Client SSH Secure Shell Client

Programs

Methods

Density Functional Theory (DFT) widely used method for theoretical

calculations of the structure of atoms, molecules, surfaces and their interactions.

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

4-methylcathinone: R1=H R2=H R3 = CH3 R4=H R5=H

4-ethylcathinone: R1= H R2=H R3= CH2CH3R4=H R5=H

3,4-dimethylethcathinone: R1=H R2=CH2CH3R3= 3,4 CH3 R4=H

4-methylcathinone

4-ethylcathinone

3,4-dimethylethcathinone

cathinone

1.225 Å

1.224 Å

1.225 Å

1.225 Å

Modeled Structures-Compounds of Known Biological Activity

Butylone Methylone

Mephedrone

{1}

{2}

{3}

Results and Discussion: Calculated Properties

Compounds E Ta E HOMO

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

a Total molecular energy (hartrees)b 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

Results

Compounds a μ f η g σ h ω i Polarizability O1j N1k

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

Mephedrone 3-0.11181 0.21221 0.78779 -0.02946 249.16 -0.55 -0.697

f Calculated chemical potential (negative of the electronegativity)

μ = (ELUMO + EHOMO)/2

 g Chemical hardness

η = (ELUMO – EHOMO)/2

h Chemical softnessσ = 1 – η i electrophilicityω = μ2/2η

j Natural Bond Orbital (NBO) calculated charge of carbonyl oxygen

k NBO calculated charge of nitrogen in amine group

ResultsDescriptors vs. 5-HT IC-50

Polarizability

IC50 = 0.0145P - 3.392N=3 R2=0.8487

ResultsDescriptors vs. Dopamine

Nitrogen Charge Polarizability

IC50 = -85NC – 58.08N=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 validationIncrease 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-cathinones- bath-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-bath- salts/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-the- cannibalism-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-drug- bust>.

[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-bath- salts.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-down- the-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-told- to-respect-culture-and-history-of-anyone-caught-chewing-the-drug-after-ban-comes-into- force/>.

[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.HolmesDr. Dwayne DanielsDr. Robin Bright