Substituted β-hydroxyamphetamines, or simply β-hydroxyamphetamines, also known as phenylisopropanolamines, phenylpropanolamines, norephedrines, or cathinols, are derivatives of β-hydroxyamphetamine with one or more chemical substituents. They are substituted phenethylamines, phenylethanolamines (β-hydroxyphenethylamines), and amphetamines (α-methylphenethylamines), and are closely related to but distinct from the substituted cathinones (β-ketoamphetamines). Examples of β-hydroxyamphetamines include the β-hydroxyamphetamine stereoisomers phenylpropanolamine and cathine and the stereospecific N-methylated β-hydroxyamphetamine derivatives ephedrine and pseudoephedrine, among many others.

In terms of pharmacological activity, the β-hydroxyamphetamines include indirectly acting norepinephrine and dopamine releasing agents and directly acting α- and β-adrenergic receptor agonists, among other actions. In contrast to their amphetamine counterparts, ephedrine and 4-fluoroephedrine are not agonists of the human trace amine-associated receptor 1 (TAAR1). With regard to medical and other uses, β-hydroxyamphetamines are employed as sympathomimetics, decongestants, bronchodilators, vasoconstrictors, vasodilators, tocolytics, antitussives, cardiac stimulants, antihypotensive agents, appetite suppressants, psychostimulants, wakefulness-promoting agents, antidepressants, euphoriants or recreational drugs, and performance-enhancing drugs (in exercise and sports), among others.

β-Hydroxyamphetamines have increased hydrophilicity and lower lipophilicity relative to their amphetamine counterparts owing to their β-hydroxyl group. For comparison, the predicted log P (XLogP3) of amphetamine is 1.8, of β-hydroxyamphetamine is 0.8, and of cathinone is 1.1. As a result of their reduced lipophilicity, they are generally less able to cross the blood–brain barrier and show greater peripheral selectivity in comparison to the corresponding amphetamine analogues. This makes the β-hydroxyamphetamines less applicable for use as centrally-acting agents but more applicable for peripherally-specific uses such as sympathomimetic stimulation. Besides different physicochemical properties, there is also a large drop in the potency of β-hydroxyamphetamines as monoamine releasing agents in vitro relative to amphetamines and cathinones.

List of substituted β-hydroxyamphetamines

Generic or Trivial Name Chemical Name # of Subs β-Hydroxyamphetamine (phenylisopropanolamine) β-Hydroxy-α-methylphenethylamine 0 Phenylpropanolamine (PPA; norephedrine) β-Hydroxyamphetamine, (1RS,2SR)- 0 (1R,2S)-Phenylpropanolamine β-Hydroxyamphetamine, (1R,2S)- 0 (1S,2R)-Phenylpropanolamine β-Hydroxyamphetamine, (1S,2R)- 0 Norpseudoephedrine β-Hydroxyamphetamine, (1SR,2RS)- 0 Cathine (D-norpseudoephedrine) β-Hydroxyamphetamine, (1S,2S)- 0 L-Norpseudoephedrine β-Hydroxyamphetamine, (1R,2R)- 0 β-Hydroxy-N-methylamphetamine β-Hydroxy-N-methylamphetamine 1 Racephedrine (racemic ephedrine) β-Hydroxy-N-methylamphetamine, (1RS,2SR)- 1 Ephedrine β-Hydroxy-N-methylamphetamine, (1R,2S)- 1 (1S,2R)-Ephedrine β-Hydroxy-N-methylamphetamine, (1S,2R)- 1 Racemic pseudoephedrine β-Hydroxy-N-methylamphetamine, (1RS,2RS)- 1 Pseudoephedrine β-Hydroxy-N-methylamphetamine, (1S,2S)- 1 (1R,2R)-Pseudoephedrine β-Hydroxy-N-methylamphetamine, (1R,2R)- 1 meta-Hydroxynorephedrine 3,β-Dihydroxyamphetamine 1 Metaraminol (metaradrine) 3,β-Dihydroxyamphetamine, (1R,2S)- 1 para-Hydroxynorephedrine 4,β-Dihydroxyamphetamine 1 Oxyfedrine β-Hydroxy-N-(...)-amphetamine, (1R,2S)- 1 Alifedrine β-Hydroxy-N-(...)-amphetamine, (1R,2S)- 1 Tinofedrine β-Hydroxy-N-(3,3-di-3-thienyl)-2-propenyl)amphetamine, (1R,2S)- 1 Cafedrine (ethyltheophyllinylnorephedrine) β-Hydroxy-N-(ethyltheophyllinyl)amphetamine 1 Methylephedrine (N-methylephedrine) β-Hydroxy-N,N-dimethylamphetamine, (1R,2S)- 2 N-Methylpseudoephedrine β-Hydroxy-N,N-dimethylamphetamine, (1S,2S)- 2 Cinnamedrine (cinnamylephedrine) β-Hydroxy-N-methyl-N-cinnamylamphetamine 2 Etafedrine (ethylephedrine) β-Hydroxy-N-methyl-N-ethylamphetamine, (1R,2S)- 2 4-Fluoroephedrine 4-Fluoro-β-hydroxy-N-methylamphetamine 2 Oxilofrine (4-hydroxyephedrine) 4,β-Dihydroxy-N-methylamphetamine 2 4-Methylephedrine (dihydromephedrone) 4-Methyl-β-hydroxy-N-methylamphetamine 2 Corbadrine (levonordefrin; α-methylnorepinephrine) 3,4,β-Trihydroxyamphetamine 2 Methoxamine (methoxamedrine) 2,6-Dimethoxy-β-hydroxyamphetamine 2 Hexapradol α-Desmethyl-α-hexyl-β-hydroxy-β-phenylamphetamine 2 Erythrohydrobupropion 3-Chloro-β-hydroxy-N-tert-butylamphetamine, erythro- 2 Threohydrobupropion 3-Chloro-β-hydroxy-N-tert-butylamphetamine, threo- 2 Ritodrine 4,β-Dihydroxy-N-(4-hydroxyphenylethyl)amphetamine 2 Isoxsuprine 4,β-Dihydroxy-N-(...)-amphetamine 2 Suloctidil 4-Isopropylthio-β-hydroxy-N-octylamphetamine 2 Buphenine 4,β-Dihydroxy-N-(...)-amphetamine 2 Trecadrine β-Hydroxy-N-methyl-N-(...)-amphetamine 2 Ethylnorepinephrine (butanefrine) β,3,4-Trihydroxy-α-desmethyl-α-ethylamphetamine 3 Dioxifedrine (α-methylepinephrine; 3,4-dihydroxyephedrine) 3,4,β-Trihydroxy-N-methylamphetamine 3 Dioxethedrin (α-methyl-N-ethylnorepinephrine) 3,4,β-Trihydroxy-N-ethylamphetamine 3 Butaxamine 2,5-Dimethoxy-β-hydroxy-N-tert-butylamphetamine, (1S,2S)- 3 Isoetarine 3,4,β-Trihydroxy-α-desmethyl-α-ethyl-N-isopropylamphetamine 4 Procaterol 2,3-(...)-4,β-dihydroxy-N-isopropyl-α-desmethyl-α-ethyl-amphetamine, (1R,2S)- 5

Side-chain-cyclized substituted β-hydroxyamphetamines Some β-hydroxyamphetamines have had their side chain extended and cyclized. Examples include certain substituted phenylmorpholines like phenmetrazine and phendimetrazine and their analogues; substituted phenylmorpholines related to bupropion like radafaxine (cyclized (2S,3S)-hydroxybupropion) and manifaxine; certain substituted aminorexes like 4-methylaminorex and 4,4'-dimethylaminorex; and other compounds including cilobamine, diphenylprolinol, ifenprodil, levophacetoperane, pipradrol, rimiterol, traxoprodil, vibegron, and zilpaterol.

Activity profiles

+ Monoamine release by β-hydroxyamphetamines and related agents (, nM) Compound Class Ref Amphetamine Amphetamine Dextroamphetamine (S(+)-amphetamine) 6.6–7.2 5.8–24.8 698–1765 Amphetamine Levoamphetamine (R(–)-amphetamine) Amphetamine Methamphetamine Amphetamine Dextromethamphetamine (S(+)-methamphetamine) 12.3–13.8 8.5–24.5 736–1291.7 Amphetamine Levomethamphetamine (R(–)-methamphetamine) 28.5 416 4640 Amphetamine Cathinone Cathinone S(–)-Cathinone (L-cathinone) 12.4 18.5 2366 Cathinone Methcathinone Cathinone L-Methcathinone 13.1 14.8 1772 Cathinone Phenylpropanolamine (norephedrine) β-Hydroxyamphetamine (+)-Phenylpropanolamine ((+)-norephedrine) 42.1 302 >10000 β-Hydroxyamphetamine (–)-Phenylpropanolamine ((–)-norephedrine) 137 1371 >10000 β-Hydroxyamphetamine Norpseudoephedrine β-Hydroxyamphetamine Cathine ((+)-norpseudoephedrine) 15.0 68.3 >10000 β-Hydroxyamphetamine (–)-Norpseudoephedrine 30.1 294 >10000 β-Hydroxyamphetamine Racephedrine (racemic ephedrine) β-Hydroxyamphetamine Ephedrine ((–)-ephedrine) 43.1–72.4 236–1350 >10000 β-Hydroxyamphetamine (+)-Ephedrine 218 2104 >10000 β-Hydroxyamphetamine Racemic pseudoephedrine β-Hydroxyamphetamine (–)-Pseudoephedrine 4092 9125 >10000 β-Hydroxyamphetamine Pseudoephedrine ((+)-pseudoephedrine) 224 1988 >10000 β-Hydroxyamphetamine The smaller the value, the more strongly the substance releases the neurotransmitter. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds.

See also Substituted amphetamine Substituted methylenedioxyphenethylamine Substituted cathinone Substituted phenylmorpholine 2Cs, DOx, 25-NB Substituted benzofurans List of aminorex analogues List of methylphenidate analogues Substituted tryptamine Substituted α-alkyltryptamines PiHKAL

References