Substituted β-hydroxyamphetamines, also known as substituted phenylisopropanolamines, substituted phenylpropanolamines, substituted norephedrines, or substituted cathinols, are derivatives of β-hydroxyamphetamine with one or more chemical substituents.[1][2][3][4] They are substituted phenethylamines, phenylethanolamines (β-hydroxyphenethylamines), and amphetamines (α-methylphenethylamines), and are closely related to but distinct from the substituted cathinones (β-ketoamphetamines).[1][2][3][5] 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.[1][2]
| Substituted β-hydroxyamphetamines | |
|---|---|
| Drug class | |
 Racemic β-hydroxyamphetamine skeleton | |
| Class identifiers | |
| Synonyms | Substituted phenylisopropanolamines; Substituted phenylpropanolamines; Substituted norephedrines; Substituted amphetanolamines; Substituted cathinols; Substituted cathines |
| Chemical class | Substituted derivatives of β-hydroxyamphetamine |
| Legal status | |
| In Wikidata | |
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.[6][7][8][9][10][1][2] In contrast to their amphetamine counterparts, ephedrine and 4-fluoroephedrine are not agonists of the human trace amine-associated receptor 1 (TAAR1).[11] 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.[1][2][9][3][10]
β-Hydroxyamphetamines have increased hydrophilicity and lower lipophilicity relative to their amphetamine counterparts owing to their β-hydroxyl group.[12][13] For comparison, the predicted log P (XLogP3) of amphetamine is 1.8,[14] of β-hydroxyamphetamine is 0.8,[15] and of cathinone is 1.1.[16] 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.[12][13][17][18] This makes the β-hydroxyamphetamines less applicable for use as centrally-acting agents but more applicable for peripherally-specific uses such as sympathomimetic stimulation.[12][13][17][18] 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.[6][8][19][20]
| 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 |
| 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 | 3,6-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
editSome 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
edit| Compound | NE | DA | 5-HT | Class | Ref | |
|---|---|---|---|---|---|---|
| Amphetamine | ND | ND | ND | Amphetamine | ND | |
| Dextroamphetamine (S(+)-amphetamine) | 6.6–7.2 | 5.8–24.8 | 698–1765 | Amphetamine | [20][21] | |
| Levoamphetamine (R(–)-amphetamine) | ND | ND | ND | Amphetamine | ND | |
| Methamphetamine | ND | ND | ND | Amphetamine | ND | |
| Dextromethamphetamine (S(+)-methamphetamine) | 12.3–13.8 | 8.5–24.5 | 736–1291.7 | Amphetamine | [20][22] | |
| Levomethamphetamine (R(–)-methamphetamine) | 28.5 | 416 | 4640 | Amphetamine | [20] | |
| Cathinone | ND | ND | ND | Cathinone | ND | |
| S(–)-Cathinone (L-cathinone) | 12.4 | 18.5 | 2366 | Cathinone | [19] | |
| Methcathinone | ND | ND | ND | Cathinone | ND | |
| L-Methcathinone | 13.1 | 14.8 | 1772 | Cathinone | [19] | |
| Phenylpropanolamine (norephedrine) | ND | ND | ND | β-Hydroxyamphetamine | ND | |
| (+)-Phenylpropanolamine ((+)-norephedrine) | 42.1 | 302 | >10000 | β-Hydroxyamphetamine | [19] | |
| (–)-Phenylpropanolamine ((–)-norephedrine) | 137 | 1371 | >10000 | β-Hydroxyamphetamine | [19] | |
| Norpseudoephedrine | ND | ND | ND | β-Hydroxyamphetamine | ND | |
| Cathine ((+)-norpseudoephedrine) | 15.0 | 68.3 | >10000 | β-Hydroxyamphetamine | [19] | |
| (–)-Norpseudoephedrine | 30.1 | 294 | >10000 | β-Hydroxyamphetamine | [19] | |
| Racephedrine (racemic ephedrine) | ND | ND | ND | β-Hydroxyamphetamine | ND | |
| Ephedrine ((–)-ephedrine) | 43.1–72.4 | 236–1350 | >10000 | β-Hydroxyamphetamine | [20] | |
| (+)-Ephedrine | 218 | 2104 | >10000 | β-Hydroxyamphetamine | [20][19] | |
| Racemic pseudoephedrine | ND | ND | ND | β-Hydroxyamphetamine | ND | |
| (–)-Pseudoephedrine | 4092 | 9125 | >10000 | β-Hydroxyamphetamine | [19] | |
| Pseudoephedrine ((+)-pseudoephedrine) | 224 | 1988 | >10000 | β-Hydroxyamphetamine | [19] | |
| 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
editReferences
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Phenylpropanolamine is a synthetic phenylisopropanolamine structurally similar to amphetamine and ephedrine. It directly stimulates α-adrenergic receptors, indirectly stimulates α- and β-adrenergic receptors by increasing release of stored norepinephrine from presynaptic sites, and partly inhibits monoamine oxidase, an enzyme responsible for catecholamine catabolism. By stimulating α-adrenergic receptors, phenylpropanolamine produces vasoconstriction within the respiratory mucosa, resulting in reduction of tissue hyperemia and shrinkage of edematous mucosal membranes.
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In 1975, cathinone [(β-ketoamphetamine)] was identified as the active stimulant component in the Catha edulis shrub. Prior to this discovery, it was believed that the psychostimulant effect of the plant was mainly attributed to cathine (β-hydroxyamphetamine), first isolated from the khat plant in 1930,127 and later described as a central stimulant.128
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- ^ "2-Amino-1-phenyl-1-propanol". PubChem. U.S. National Library of Medicine. Retrieved 2 September 2024.
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Lipophilicity was the first of the descriptors to be identified as important for CNS penetration. Hansch and Leo54 reasoned that highly lipophilic molecules will partitioned into the lipid interior of membranes and will be retained there. However, ClogP correlates nicely with LogBBB with increasing lipophilicity increasing brain penetration. For several classes of CNS active substances, Hansch and Leo54 found that blood-brain barrier penetration is optimal when the LogP values are in the range of 1.5-2.7, with the mean value of 2.1. An analysis of small drug-like molecules suggested that for better brain permeation46 and for good intestinal permeability55 the LogD values need to be greater than 0 and less than 3. In comparison, the mean value for ClogP for the marketed CNS drugs is 2.5, which is in good agreement with the range found by Hansch et al.22
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