| Substituted amphetamine | |
|---|---|
| Drug class | |
 Racemic amphetamine skeleton | |
| Class identifiers | |
| Synonyms | Amphetamines; α-Methylphenethylamines; α-Methylphenylethylamines; Phenylisopropylamines |
| Chemical class | Substituted derivatives of amphetamine |
| Legal status | |
| In Wikidata | |
 |  |
 |  |
| L-amphetamine | D-amphetamine |
Substituted amphetamines, or simplyamphetamines, are aclass of compounds based upon theamphetamine structure;[1] it includes allderivative compounds which are formed by replacing, orsubstituting, one or morehydrogen atoms in the amphetamine core structure withsubstituents.[1][2][3][4] The compounds in this class span a variety of pharmacological subclasses, includingstimulants,empathogens, andhallucinogens, among others.[2] Examples of substituted amphetamines are amphetamine (itself),[1][2]methamphetamine,[1]ephedrine,[1]cathinone,[1]phentermine,[1]mephentermine,[1]tranylcypromine,[5]bupropion,[1]methoxyphenamine,[1]selegiline,[1]amfepramone (diethylpropion),[1]pyrovalerone,[1]MDMA (ecstasy), andDOM (STP).
Some of amphetamine's substitutedderivatives occur in nature, for example in the leaves ofEphedra andkhat plants.[1] Amphetamine was first produced at the end of the 19th century. By the 1930s,amphetamine and some of itsderivative compounds found use as decongestants in the symptomatic treatment ofcolds and also occasionally as psychoactive agents. Their effects on thecentral nervous system are diverse, but can be summarized by three overlapping types of activity:psychoanaleptic,hallucinogenic andempathogenic. Various substituted amphetamines may cause these actions either separately or in combination.
| Generic or Trivial Name | Chemical Name | # of Subs |
|---|---|---|
| Amphetamine | α-Methyl-phenethylamine | 0 |
| Tranylcypromine | trans-2-Phenylcyclopropylamine | 0[note 1] |
| Methamphetamine | N-Methylamphetamine | 1 |
| Ethylamphetamine | N-Ethylamphetamine | 1 |
| Propylamphetamine | N-Propylamphetamine | 1 |
| Isopropylamphetamine | N-iso-Propylamphetamine | 1 |
| Butylamphetamine | N-n-Butylamphetamine | 1 |
| Pheniprazine | N-Aminoamphetamine | 1 |
| Phenatine | N-Nicotinoylamphetamine | 1 |
| Lisdexamfetamine | L-Lysine–amphetamine conjugate, (S)- | 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 |
| 2-Phenyl-3-aminobutane | 2-Phenyl-3-aminobutane | 1 |
| 3-Fluoroamphetamine (3-FA) | 3-Fluoroamphetamine | 1 |
| Gepefrine | 3-Hydroxyamphetamine | 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 |
| Mefenorex | N-(3-Chloropropyl)amphetamine | 1 |
| Clobenzorex | N-(2-Chlorobenzyl)amphetamine | 1 |
| Amfetaminil | N-Cyanobenzylamphetamine | 1 |
| Amfecloral | N-(2,2,2-Trichloroethylidene)amphetamine | 1 |
| Racefemine | N-(1-Methyl-2-phenoxyethyl)amphetamine | 1 |
| Dextrofemine | N-(1-Methyl-2-phenoxyethyl)amphetamine, (+)- | 1 |
| Fenproporex | N-2-Cyanoethylamphetamine | 1 |
| Prenylamine | N-(3,3-Diphenylpropyl)amphetamine | 1 |
| Fenethylline | Theophylline–amphetamine conjugate | 1 |
| Dimethylamphetamine | N,N-Dimethylamphetamine | 2 |
| Benzphetamine | N-Benzyl-N-methylamphetamine | 2 |
| Deprenyl | N-Methyl-N-propargylamphetamine | 2 |
| D-Deprenyl | N-Methyl-N-propargylamphetamine, (S)- | 2 |
| Selegiline | N-Methyl-N-propargylamphetamine, (R)- | 2 |
| Metfendrazine | N-Amino-N-methylamphetamine | 2 |
| Mephentermine | N-Methyl-α-methylamphetamine | 2 |
| Phenpentermine | α,β-Dimethylamphetamine | 2 |
| Ephedrine | β-Hydroxy-N-methylamphetamine, (1R,2S)- | 2 |
| Pseudoephedrine (PSE) | β-Hydroxy-N-methylamphetamine, (1S,2S)- | 2 |
| Metaraminol | 3,β-Dihydroxyamphetamine, (1R,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 |
| 3,4-Methylenedioxyamphetamine (MDA) | 3,4-Methylenedioxyamphetamine | 2 |
| Dimethoxyamphetamine (DMA) | X,X-Dimethoxyamphetamine | 2 |
| 6-APB | 6-(2-Aminopropyl)benzofuran | 2 |
| Phenylpropylaminopentane (PPAP) | α-Desmethyl-α,N-dipropylamphetamine | 2 |
| Furfenorex | N-(2-Furylmethyl)-N-methylamphetamine | 2 |
| Fencamine | 8-Aminocaffeine–methamphetamine conjugate | 2 |
| Nordefrin (α-Me-NE) | β,3,4-Trihydroxyamphetamine, (R)- | 3 |
| Methylephedrine | β-Hydroxy-N-methylamphetamine, (1R,2S)- | 3 |
| Etafedrine | β-Hydroxy-N-ethylamphetamine, (1R,2S)- | 3 |
| Oxilofrine | β,4-Dihydroxy-N-methylamphetamine | 3 |
| Cinnamedrine | β-Hydroxy-N-methyl-N-cinnamylamphetamine | 3 |
| Methoxamine | 2,6-Dimethoxy-β-hydroxyamphetamine | 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 |
| Ritodrine | 4,β-Dihydroxy-N-(4-hydroxyphenylethyl)amphetamine | 3 |
| Buphenine (nylidrin) | 4,β-Dihydroxy-N-(...)-amphetamine | 3 |
| Trecadrine | β-Hydroxy-N-methyl-N-(...)-amphetamine | 3 |
| Isoxsuprine | 4,β-Dihydroxy-N-(...)-amphetamine | 3 |
| Dioxifedrine | 3,4,β-Trihydroxy-N-methylamphetamine | 4 |
| Dioxethedrin | 3,4,β-Trihydroxy-N-ethylamphetamine | 4 |
A variety ofprodrugs ofamphetamine and/ormethamphetamine exist, and includeamfecloral,amfetaminil,benzphetamine,clobenzorex,D-deprenyl,deprenyl,dimethylamphetamine,ethylamphetamine,fencamine,fenethylline,fenproporex,furfenorex,lisdexamfetamine,mefenorex,prenylamine, andselegiline.[6]
A number ofsyntheticRussian amphetamine derivatives have been developed, includingalafen (amphetamine–β-alanine),feprosidnine,gamofen (amphetamine–GABA),mesocarb,methylphenatine,pabofen (amphetamine–PABA),phenatine (amphetamine–niacin;N-nicotinoylamphetamine),phenylphenamine (phenylamphetamine),propylphenamine (propylamphetamine),pyridoxiphen (amphetamine–pyridoxine), andthiophenatine (N-thionicotinoylamphetamine).
![[icon]](/mt/?noimg=&dark=on&url=http%3a%2f%2fwww.wikipedia.org%2fwiki%2fFile%3aWiki_letter_w_cropped.svg) | This sectionneeds expansion with: substituents and structures forphenelzine,phenylephrine,phenylpropanolamine,selegiline,fenfluramine,mescaline,diethylpropion,desmethylselegiline, andbenzphetamine fromthis table.[7]. You can help byadding to it.(February 2019) |
Amphetamines are a subgroup of thesubstituted phenethylamine class of compounds. Substitution of hydrogen atoms results in a large class of compounds. Typical reaction is substitution bymethyl and sometimesethyl groups at theamine andphenyl sites:[8][9][10]
| Substance | Substituents | Structure | Sources | ||||||
|---|---|---|---|---|---|---|---|---|---|
| N | α | β | phenyl group | ||||||
| 2 | 3 | 4 | 5 | ||||||
| Phenethylamine |  | ||||||||
| Amphetamine (α-methylphenylethylamine) | -CH3 |  | [7] | ||||||
| Methamphetamine (N-methylamphetamine) | -CH3 | -CH3 |  | [7] | |||||
| Phentermine (α-methylamphetamine) | -(CH3)2 |  | [7] | ||||||
| Ephedrine | -CH3 | -CH3 | -OH | -Ephedrin.svg) | [7] | ||||
| Pseudoephedrine | -CH3 | -CH3 | -OH | -Pseudoephedrin.svg) | [7] | ||||
| Cathinone | -CH3 | =O |  | [7] | |||||
| Methcathinone (ephedrone) | -CH3 | -CH3 | =O |  | [7] | ||||
| MDA (3,4-methylenedioxyamphetamine) | -CH3 | -O-CH2-O- |  | [7] | |||||
| MDMA (3,4-methylenedioxymethamphetamine) | -CH3 | -CH3 | -O-CH2-O- | .svg) | [7] | ||||
| MDEA (3,4-methylenedioxy-N-ethylamphetamine) | -CH2-CH3 | -CH3 | -O-CH2-O- |  | [7] | ||||
| EDMA (3,4-ethylenedioxy-N-methylamphetamine) | -CH3 | -CH3 | -O-CH2-CH2-O- |  | |||||
| MBDB (N-methyl-1,3-benzodioxolylbutanamine) | -CH3 | -CH2-CH3 | -O-CH2-O- |  | |||||
| PMA (para-methoxyamphetamine) | -CH3 | -O-CH3 |  | ||||||
| PMMA (para-methoxymethamphetamine) | -CH3 | -CH3 | -O-CH3 |  | |||||
| 4-MTA (4-methylthioamphetamine) | -CH3 | -S-CH3 |  | ||||||
| 3,4-DMA (3,4-dimethoxyamphetamine) | -CH3 | -O-CH3 | -O-CH3 |  | |||||
| 3,4,5-Trimethoxyamphetamine (α-methylmescaline) | -CH3 | -O-CH3 | -O-CH3 | -O-CH3 |  | ||||
| DOM (2,5-dimethoxy-4-methylamphetamine) | -CH3 | -O-CH3 | -CH3 | -O-CH3 |  | ||||
| DOB (2,5-dimethoxy-4-bromoamphetamine) | -CH3 | -O-CH3 | -Br | -O-CH3 |  | ||||
Ephedra was used 5000 years ago in China as amedicinal plant; its active ingredients arealkaloids ephedrine,pseudoephedrine,norephedrine (phenylpropanolamine) andnorpseudoephedrine (cathine). Natives ofYemen andEthiopia have a long tradition of chewingkhat leaves to achieve a stimulating effect. The active substances of khat arecathinone and, to a lesser extent,cathine.[11]
Amphetamine was first synthesized in 1887 byRomanian chemistLazăr Edeleanu, although its pharmacological effects remained unknown until the 1930s.[12] MDMA was produced in 1912 (in 1914, according to other sources[13]) as an intermediate product. However, this synthesis also went largely unnoticed.[14] In the 1920s, both methamphetamine and the dextrorotatory optical isomer of amphetamine,dextroamphetamine, were synthesized. This synthesis was a by-product of a search for ephedrine, a bronchodilator used to treatasthma extracted exclusively from natural sources. Over-the-counter use of substituted amphetamines was initiated in the early 1930s by the pharmaceutical company Smith, Kline & French (now part ofGlaxoSmithKline), as a medicine (Benzedrine) forcolds andnasal congestion. Subsequently, amphetamine was used in the treatment ofnarcolepsy,obesity,hay fever,orthostatic hypotension,epilepsy,Parkinson's disease,alcoholism andmigraine.[12][15] The "reinforcing" effects of substituted amphetamines were quickly discovered, and the misuse of substituted amphetamines had been noted as far back as 1936.[15]
DuringWorld War II, amphetamines were used by the German military to keep their tank crews awake for long periods, and treatdepression. It was noticed that extended rest was required after such artificially induced activity.[12] The widespread use of substituted amphetamines began in postwarJapan and quickly spread to other countries. Modified "designer amphetamines", such asMDA andPMA, have gained in popularity since the 1960s.[15] In 1970, theUnited States adopted "the Controlled Substances Act" that limited non-medical use of substituted amphetamines.[15] Street use of PMA was noted in 1972.[16] MDMA emerged as a substitute for MDA in the early 1970s.[17] American chemistAlexander Shulgin first synthesized the drug in 1976 and through him the drug was briefly introduced into psychotherapy.[18] Recreational use grew and in 1985 MDMA was banned by the US authorities in an emergency scheduling initiated by theDrug Enforcement Administration.[19]
Since the mid-1990s, MDMA has become a popularentactogenic drug among the youth and quite often non-MDMA substances were sold as ecstasy.[20] Ongoing trials are investigating its efficacy as an adjunct to psychotherapy in the management of treatment-resistant post-traumatic stress disorder (PTSD).[21]
| Agents | Legal status by 2009.[22][23][24][25] | |||
|---|---|---|---|---|
| US | Russia | Australia | ||
| Amphetamine (racemic) | Schedule II | Schedule II | Schedule II | Schedule 8 |
| Dextroamphetamine (D-amphetamine) | Schedule II | Schedule II | Schedule I | Schedule 8 |
| Levoamphetamine (L-amphetamine) | Schedule II | Schedule II | Schedule III | Schedule 8 |
| Methamphetamine | Schedule II | Schedule II | Schedule I | Schedule 8 |
| CathinoneMethcathinone | Schedule I | Schedule I | Schedule I | Schedule 9 |
| MDA,MDMA,MDEA | Schedule I | Schedule I | Schedule I | Schedule 9 |
| PMA | Schedule I | Schedule I | Schedule I | Schedule 9 |
| DOB,DOM,3,4,5-TMA | Schedule I | Schedule I | Schedule I | Schedule 9 |
Substituted amphetamines, which are also called phenylpropylamino alkaloids, are a diverse group of nitrogen-containing compounds that feature a phenethylamine backbone with a methyl group at the α-position relative to the nitrogen (Figure 1). Countless variation in functional group substitutions has yielded a collection of synthetic drugs with diverse pharmacological properties as stimulants, empathogens and hallucinogens [3]. ... Beyond (1R,2S)-ephedrine and (1S,2S)-pseudoephedrine, myriad other substituted amphetamines have important pharmaceutical applications. The stereochemistry at the α-carbon is often a key determinant of pharmacological activity, with (S)-enantiomers being more potent. For example, (S)-amphetamine, commonly known as d-amphetamine or dextroamphetamine, displays five times greater psychostimulant activity compared with its (R)-isomer [78]. Most such molecules are produced exclusively through chemical syntheses and many are prescribed widely in modern medicine. For example, (S)-amphetamine (Figure 4b), a key ingredient in Adderall and Dexedrine, is used to treat attention deficit hyperactivity disorder (ADHD) [79]. ...
[Figure 4](b) Examples of synthetic, pharmaceutically important substituted amphetamines.
The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39).
Media related toAmphetamines at Wikimedia Commons
