Substituted amphetamine

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"Amphetamines" redirects here. For the chemical, see Amphetamine. For other uses, see Amphetamine (disambiguation).
Optical isomers of amphetamine

Substituted amphetamines are a chemical class of stimulants, entactogens, hallucinogens, and other drugs. They feature a phenethylamine core with a methyl group attached to the alpha carbon resulting in amphetamine, along with additional substitutions. Examples of amphetamines are amphetamine (itself), methamphetamine, ephedrine, cathinone, MDMA ("Ecstasy"), and DOM ("STP").

Amphetamine derivatives occur in nature, for example in the leaves of Ephedra and khat plants. These have been used since antiquity for their pharmacological effects. Amphetamines were first produced synthetically at the end of the 19th century. By the 1930s such synthetic amphetamines found use as decongestants in the symptomatic treatment of colds and also occasionally as psychoactive agents. Their effects on the central nervous system are diverse, but can be summarized by three overlapping types of activity: psychoanaleptic, hallucinogenic and empathogenic. Various amphetamines may cause these actions either separately or in combination.

List of substituted amphetamines[edit]

Structural formula of amphetamine
Generic or Trivial Name Chemical Name # of Subs Comments Reference(s)
Amphetamine α-Methyl-phenethylamine 0
Methamphetamine N-Methylamphetamine, (1R,2S)- 1
Ethylamphetamine N-Ethylamphetamine 1
Propylamphetamine N-Propylamphetamine 1
Isopropylamphetamine N-iso-Propylamphetamine 1
Phentermine α-Methylamphetamine 1
Phenylpropanolamine (PPA) β-Hydroxyamphetamine, (1R,2S)- 1
Cathine β-Hydroxyamphetamine, (1S,2S)- 1
Cathinone β-Ketoamphetamine 1
Ortetamine 2-Methylamphetamine 1
2-Fluoroamphetamine (2-FA) 2-Fluoroamphetamine 1
3-Methylamphetamine (3-MA) 3-Methylamphetamine 1
3-Fluoroamphetamine (3-FA) 3-Fluoroamphetamine 1
Norfenfluramine 3-Trifluoromethylamphetamine 1
4-Methylamphetamine (4-MA) 4-Methylamphetamine 1
para-Methoxyamphetamine (PMA) 4-Methoxyamphetamine 1
para-Ethoxyamphetamine 4-Ethoxyamphetamine 1
4-Methylthioamphetamine (4-MTA) 4-Methylthioamphetamine 1
Norpholedrine (α-Me-TRA) 4-Hydroxyamphetamine 1
para-Bromoamphetamine (PBA, 4-BA) 4-Bromoamphetamine 1
para-Chloroamphetamine (PCA, 4-CA) 4-Chloroamphetamine 1
para-Fluoroamphetamine (PFA, 4-FA, 4-FMP) 4-Fluoroamphetamine 1
para-Iodoamphetamine (PIA, 4-IA) 4-Iodoamphetamine 1
Clobenzorex N-(2-chlorobenzyl)-1-phenylpropan-2-amine 1
Dimethylamphetamine N,N-Dimethylamphetamine 2
Benzphetamine N-Benzyl-N-methylamphetamine 2
Selegiline N-Methyl-N-propargylamphetamine, (R)- 2
Mephentermine N-Methyl-α-methylamphetamine 2
Phenpentermine α,β-Dimethylamphetamine 2
Ephedrine (EPH) β-Hydroxy-N-methylamphetamine, (1R,2S)- 2
Pseudoephedrine (PSE) β-Hydroxy-N-methylamphetamine, (1S,2S)- 2
Methcathinone β-Keto-N-methylamphetamine 2
Ethcathinone β-Keto-N-ethylamphetamine 2
Clortermine 2-Chloro-α-methylamphetamine 2
Methoxymethylamphetamine (MMA) 3-Methoxy-4-methylamphetamine 2
Fenfluramine 3-Trifluoromethyl-N-ethylamphetamine 2
Dexfenfluramine 3-Trifluoromethyl-N-ethylamphetamine, (S)- 2
4-Methylmethamphetamine (4-MMA) 4-Methyl-N-methylamphetamine 2
Para-methoxymethamphetamine (PMMA) 4-Methoxy-N-methylamphetamine 2
para-Methoxyethylamphetamine (PMEA) 4-Methoxy-N-ethylamphetamine 2
Pholedrine 4-Hydroxy-N-methylamphetamine 2
Chlorphentermine 4-Chloro-α-methylamphetamine 2
para-Fluoromethamphetamine (PFMA, 4-FMA) 4-Fluoro-N-methylamphetamine 2
Xylopropamine 3,4-Dimethylamphetamine 2
α-Methyldopamine (α-Me-DA) 3,4-Dihydroxyamphetamine 2
Methylenedioxyamphetamine (MDA) 3,4-Methylenedioxyamphetamine 2
Dimethoxyamphetamine (DMA) X,X-Dimethoxyamphetamine 2
Nordefrin (α-Me-NE) β,3,4-Trihydroxyamphetamine, (R)- 3
Oxilofrine β,4-Dihydroxy-N-methylamphetamine 3
Aleph 2,5-dimethoxy-4-methylthioamphetamine 3
Dimethoxybromoamphetamine (DOB) 2,5-Dimethoxy-4-bromoamphetamine 3
Dimethoxychloroamphetamine (DOC) 2,5-Dimethoxy-4-chloroamphetamine 3
Dimethoxyfluoroethylamphetamine (DOEF) 2,5-Dimethoxy-4-fluoroethylamphetamine 3
Dimethoxyethylamphetamine (DOET) 2,5-Dimethoxy-4-ethylamphetamine 3
Dimethoxyfluoroamphetamine (DOF) 2,5-Dimethoxy-4-fluoroamphetamine 3
Dimethoxyiodoamphetamine (DOI) 2,5-Dimethoxy-4-iodoamphetamine 3
Dimethoxymethylamphetamine (DOM) 2,5-Dimethoxy-4-methylamphetamine 3
Dimethoxynitroamphetamine (DON) 2,5-Dimethoxy-4-nitroamphetamine 3
Dimethoxypropylamphetamine (DOPR) 2,5-Dimethoxy-4-propylamphetamine 3
Dimethoxytrifluoromethylamphetamine (DOTFM) 2,5-Dimethoxy-4-trifluoromethylamphetamine 3
Methylenedioxymethamphetamine (MDMA) 3,4-Methylenedioxy-N-methylamphetamine 3
Methylenedioxyethylamphetamine (MDEA) 3,4-Methylenedioxy-N-ethylamphetamine 3
Methylenedioxyhydroxyamphetamine (MDOH) 3,4-Methylenedioxy-N-hydroxyamphetamine 3
2-Methyl-MDA 3,4-Methylenedioxy-2-methylamphetamine 3
5-Methyl-MDA 4,5-Methylenedioxy-3-methylamphetamine 3
Methoxymethylenedioxyamphetamine (MMDA) 3-Methoxy-4,5-methylenedioxyamphetamine 3
Trimethoxyamphetamine (TMA) X,X,X-Trimethoxyamphetamine 3
Dimethylcathinone β-Keto-N,N-dimethylamphetamine 3
Diethylcathinone β-Keto-N,N-diethylamphetamine 3
Bupropion β-Keto-3-chloro-N-tert-butylamphetamine 3
Mephedrone (4-MMC) β-Keto-4-methyl-N-methylamphetamine 3
Methedrone (PMMC) β-Keto-4-methoxy-N-methylamphetamine 3
Brephedrone (4-BMC) β-Keto-4-bromo-N-methylamphetamine 3
Flephedrone (4-FMC) β-Keto-4-fluoro-N-methylamphetamine 3

History[edit]

Although the basic compound of the class, amphetamine, was synthesized earlier, Ephedra was used 5000 years ago in China as a medicinal plant; its active ingredients are alkaloids ephedrine, pseudoephedrine, norephedrine (phenylpropanolamine) and norpseudoephedrine (cathine). Natives of Yemen and Ethiopia have a long tradition of chewing khat leaves to achieve a stimulating effect. The active substances of khat are cathinone and to a lesser extent cathine.[1]

Amphetamine was first synthesized in 1887 by Romanian chemist Lazăr Edeleanu and did not attract special attention.[2] MDMA was produced in 1912 (according to other sources in 1914[3]) as an intermediate product. However, this synthesis also went largely unnoticed.[4] In the 1920s, both methamphetamine and an optical isomer of amphetamine dextroamphetamine (D-amphetamines) were synthesized. This synthesis was a by-product of a search for ephedrine, a bronchodilator used to treat asthma extracted exclusively from natural sources. Over-the-counter use of amphetamines was initiated in early 1930s by the pharmaceutical company Smith, Kline & French (now part of GlaxoSmithKline), as a medicine (Benzedrine) for colds and nasal congestion. Subsequently, amphetamine was used in the treatment of narcolepsy, obesity, hay fever, orthostatic hypotension, epilepsy, Parkinson's disease, alcoholism and migraine.[2][5] The "reinforcing" effects of amphetamines were quickly discovered, and the misuse of amphetamines had been noted as far back as 1936.[5]

During World War II, amphetamines were used by the German military to keep their tank crews awake for long periods, and treat depression. It was noticed that extended rest was required after such artificially induced activity.[2]

The widespread use of amphetamines began in postwar Japan and quickly spread to other countries. Modified ("designer") amphetamines gained popularity since the 1960s, such as MDA and PMA.[5] MDMA was rediscovered and popularized by the American chemist Alexander Shulgin in 1965, after which it was used for some time in psychotherapy sessions.[4] In 1970, the United States adopted "the Controlled Substances Act" that limited non-medical use of amphetamines.[5] Street use of PMA was noted in 1972,[6] and in 1985, MDMA was banned by the US authorities in an emergency scheduling initiated by the US Drug Enforcement Agency.[7]

Since the mid-1990s, MDMA ("ecstasy") has become a popular entactogenic drug among the youth and quite often non-MDMA substances were sold as "ecstasy".[8] In the first legally sanctioned trials in the USA in over twenty years, the safety profile of MDMA has been demonstrated, and it has been shown to be a successful adjunct to psychotherapy in the management of treatment-resistant post-traumatic stress disorder (PTSD) in victims of sexual abuse and sufferers of other conditions.[9]

Structure[edit]

Amphetamines are a subgroup of the substituted phenethylamine class of compounds. Substitution of hydrogen atoms results in a large class of compounds. Typical reaction is substitution by methyl and sometimes ethyl groups at the amine and phenyl sites:[10][11][12]

Substance Substituents Structure
N α β phenyl group
2 3 4 5
Amphetamine (α-methylphenylethylamine) -CH3 Amphetamine
Methamphetamine (N-methylamphetamine) -CH3 -CH3 Methamphetamine
Ephedrine pseudoephedrine -CH3 -CH3 -OH Pseudoephedrine
Cathinone -CH3 =O Cathinone
Methcathinone (ephedrone) -CH3 -CH3 =O Methcathinone
MDA (3,4-methylenedioxyamphetamine) -CH3 -O-CH2-O- 3,4-methylenedioxyamphetamine
MDMA (3,4-methylenedioxymethamphetamine) -CH3 -CH3 -O-CH2-O- 3,4-methylenedioxymethamphetamine
MDEA (3,4-methylenedioxy-N-ethylamphetamine) -CH2-CH3 -CH3 -O-CH2-O- methylenedioxyethylamphetamine
EDMA (3,4-ethylenedioxy-N-methylamphetamine) -CH3 -CH3 -O-CH2-CH2-O- 3,4-ethylenedioxy-N-methylamphetamine
MBDB (N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminobutane) -CH3 -CH2-CH3 -O-CH2-O- N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminobutane
PMA (para-methoxyamphetamine) -CH3 -O-CH3 para-methoxyamphetamine
PMMA (para-methoxymethamphetamine) -CH3 -CH3 -O-CH3 para-methoxymethamphetamine
4-MTA (4-methylthioamphetamine) -CH3 -S-CH3 4-methylthioamphetamine
3,4-DMA (3,4-dimethoxyamphetamine) -CH3 -O-CH3 -O-CH3 dimethoxyamphetamine
3,4,5-TMA (3,4,5-trimethoxyamphetamine, α-methylmescaline) -CH3 -O-CH3 -O-CH3 -O-CH3 trimethoxyamphetamine
DOM (2,5-dimethoxy-4-methylamphetamine) -CH3 -O-CH3 -CH3 -O-CH3 2,5-dimethoxy-4-methylamphetamine
DOB (2,5-dimethoxy-4-bromoamphetamine) -CH3 -O-CH3 -Br -O-CH3 2,5-dimethoxy-4-bromoamphetamine

Legal status[edit]

Agents Legal status by 2009.[13][14][15]
UN Convention on Psychotropic Substances of 1971[16] US Russia
Amphetamine (racemic) Schedule II Schedule II Schedule II
Dextroamphetamine (D-amphetamine) Schedule II Schedule II Schedule I
Levamphetamine (L-amphetamine) Schedule II Schedule II Schedule III
Methamphetamine Schedule II Schedule II Schedule I
Cathinone Methcathinone Schedule I Schedule I Schedule I
MDA, MDMA, MDEA Schedule I Schedule I Schedule I
PMA Schedule I Schedule I Schedule I
DOB, DOM, 3,4,5-TMA Schedule I Schedule I Schedule I

See also[edit]

References[edit]

  1. ^ Paul M Dewick (2002). Medicinal Natural Products. A Biosynthetic Approach. Second Edition. Wiley. pp. 383–384. ISBN 0-471-49640-5. 
  2. ^ a b c Snow, p. 1
  3. ^ A. Richard Green et al. (2003). "The Pharmacology and Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy")". Pharmacological Reviews 55 (3): 463–508. doi:10.1124/pr.55.3.3. PMID 12869661. 
  4. ^ a b Goldfrank, p. 1125
  5. ^ a b c d Goldfrank, p. 1119
  6. ^ Liang Han Ling et al. (2001). "Poisoning with the recreational drug paramethoxyamphetamine ("death" )". The Medical Journal of Australia 174 (9): 453–5. PMID 11386590. 
  7. ^ Snow, p. 71
  8. ^ Goldfrank, p. 1121
  9. ^ Mithoefer M. et al. (2011). "The safety and efficacy of ±3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study". Journal of Psychopharmacology 25 (4): 439–52. doi:10.1177/0269881110378371. PMC 3122379. PMID 20643699. 
  10. ^ Gold frank, pp. 1125–1127
  11. ^ Glennon, pp. 184–187
  12. ^ Schatzberg, p.843
  13. ^ "List of psychotropic substances under international control". International Narcotics Control Board. August 2003.  May 2010 Edition
  14. ^ "DEA Drug Scheduling". U.S. Drug Enforcement Administration. Retrieved 17 November 2009. 
  15. ^ "Resolution of RF Government of 30 June 1998 N 681 "On approval of list of drugs psychotropic substances and their precursors subject to control in the Russian Federation"". garant.ru (in Russian). Retrieved 15 November 2009. 
  16. ^ "Convention on Psychotropic Substances, 1971". United Nations. 

Bibliography[edit]