Computational studies of Cathinone And cathinone derivatives

1. Computational studies of Cathinone And cathinone derivatives KiaraLipsey Mentor: Tiffani Holmes, Ph.D. Louis Stokes Alliance For Minority Participation Summer Research Program Fort Valley State University July 31, 2014

2. 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

3. 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. Khat

4. Cathinone Fig. 1. Structure of cathinone

5. 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. Synthetic Cathinones

6. 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. • Asuspect 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. Bath Salt Incidents

7. 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) Government Regulations

8. 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

9. Pharmacological Effects Cathinone and its derivatives exhibit the same effects as methamphetamines. Methamphetamines work in the brain to increase monoamine (dopamine) levelsby: • 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. 5-hydroxytryptamine dopamine MDMA (ecstacy)

10. 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

11. 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 methylmethcathinone in body fluids Ex: Methylone, butylone, and mephedrone have been found to inhibit the uptake of monoamines

12. 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.

13. 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

14. Programs Gauss View SSH Secure Shell Client

15. 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) Methods

16. 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 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 cathinone 1.225 Å 4-methylcathinone 3,4-dimethylethcathinone

17. Modeled Structures-Compounds of Known Biological Activity {1} Methylone Butylone {2} {3} Mephedrone

18. Results and Discussion: Calculated Properties 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

19. Results f Calculated chemical potential (negative of the electronegativity) μ = (ELUMO + EHOMO)/2 g Chemical hardness η = (ELUMO – EHOMO)/2 h Chemical softness σ = 1 – η i electrophilicity ω = μ2/2η j Natural Bond Orbital (NBO) calculated charge of carbonyl oxygen k NBO calculated charge of nitrogen in amine group

20. ResultsDescriptors vs. 5-HT IC-50 Polarizability IC50 = 0.0145P - 3.392 N=3 R2=0.8487

21. ResultsDescriptors vs. Dopamine Nitrogen Charge Polarizability IC50 = -85NC – 58.08 N=3 R2=0.9146

22. 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.

23. 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.

24. References

25. References

26. 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.

27. 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