| Substituted β-hydroxyamphetamines | |
|---|---|
| Drug class | |
 Racemic β-hydroxyamphetamine skeleton | |
| Class identifiers | |
| Synonyms | β-Hydroxyamphetamines; β-Hydroxyphenylisopropylamines; β-Hydroxyphenylaminopropanes; Phenylisopropanolamines; Phenylpropanolamines; Norephedrines; Amphetanolamines; Cathinols; Cathines |
| Chemical class | Substituted derivatives of β-hydroxyamphetamine |
| Legal status | |
| In Wikidata | |
Substituted β-hydroxyamphetamines, or simplyβ-hydroxyamphetamines, also known asphenylisopropanolamines,phenylpropanolamines,norephedrines, or cathinols, arederivatives ofβ-hydroxyamphetamine with one or morechemical substituents.[1][2][3][4][5] They aresubstituted phenethylamines,phenylethanolamines (β-hydroxyphenethylamines), andamphetamines (α-methylphenethylamines), and are closely related to but distinct from thesubstituted cathinones (β-ketoamphetamines).[1][2][3][4][6] Examples of β-hydroxyamphetamines include the β-hydroxyamphetaminestereoisomersphenylpropanolamine andcathine and thestereospecificN-methylated β-hydroxyamphetamine derivativesephedrine andpseudoephedrine, among many others.[1][2][3]
In terms ofpharmacological activity, the β-hydroxyamphetamines include indirectly actingnorepinephrine anddopamine releasing agents and directly actingα- andβ-adrenergic receptoragonists, among other actions.[7][8][9][10][11][2][3] In contrast to their amphetamine counterparts, ephedrine and4-fluoroephedrine are not agonists of the humantrace amine-associated receptor 1 (TAAR1).[12] With regard tomedical and other uses, β-hydroxyamphetamines are employed assympathomimetics,decongestants,bronchodilators,vasoconstrictors,vasodilators,tocolytics,antitussives,cardiac stimulants,antihypotensive agents,appetite suppressants,psychostimulants,wakefulness-promoting agents,antidepressants,euphoriants orrecreational drugs, andperformance-enhancing drugs (inexercise andsports), among others.[2][3][10][4][11]
β-Hydroxyamphetamines have increasedhydrophilicity and lowerlipophilicity relative to their amphetamine counterparts owing to their β-hydroxyl group.[13][14] For comparison, the predictedlog P (XLogP3) ofamphetamine is 1.8,[15] of β-hydroxyamphetamine is 0.8,[16] and ofcathinone is 1.1.[17] As a result of their reduced lipophilicity, they are generally less able to cross theblood–brain barrier and show greaterperipheral selectivity in comparison to the corresponding amphetamineanalogues.[13][14][18][19] This makes the β-hydroxyamphetamines less applicable for use ascentrally-acting agents but more applicable forperipherally-specific uses such as sympathomimetic stimulation.[13][14][18][19] Besides differentphysicochemical properties, there is also a large drop in thepotency of β-hydroxyamphetamines as monoamine releasing agentsin vitro relative to amphetamines and cathinones.[7][9][20][21]
| Generic or Trivial Name[2][3] | 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 |
Some β-hydroxyamphetamines have had theirside chain extended andcyclized. Examples include certainsubstituted phenylmorpholines likephenmetrazine andphendimetrazine and theiranalogues; substituted phenylmorpholines related tobupropion likeradafaxine (cyclized (2S,3S)-hydroxybupropion) andmanifaxine; certainsubstituted aminorexes like4-methylaminorex and4,4'-dimethylaminorex; and othercompounds includingcilobamine,diphenylprolinol,ifenprodil,levophacetoperane,pipradrol,rimiterol,traxoprodil,vibegron, andzilpaterol.
| Compound | NETooltip Norepinephrine | DATooltip Dopamine | 5-HTTooltip Serotonin | Class | Ref | |
|---|---|---|---|---|---|---|
| Amphetamine | ND | ND | ND | Amphetamine | ND | |
| Dextroamphetamine (S(+)-amphetamine) | 6.6–7.2 | 5.8–24.8 | 698–1765 | Amphetamine | [21][22] | |
| 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 | [21][23] | |
| Levomethamphetamine (R(–)-methamphetamine) | 28.5 | 416 | 4640 | Amphetamine | [21] | |
| Cathinone | ND | ND | ND | Cathinone | ND | |
| S(–)-Cathinone (L-cathinone) | 12.4 | 18.5 | 2366 | Cathinone | [20] | |
| Methcathinone | ND | ND | ND | Cathinone | ND | |
| L-Methcathinone | 13.1 | 14.8 | 1772 | Cathinone | [20] | |
| Phenylpropanolamine (norephedrine) | ND | ND | ND | β-Hydroxyamphetamine | ND | |
| (+)-Phenylpropanolamine ((+)-norephedrine) | 42.1 | 302 | >10000 | β-Hydroxyamphetamine | [20] | |
| (–)-Phenylpropanolamine ((–)-norephedrine) | 137 | 1371 | >10000 | β-Hydroxyamphetamine | [20] | |
| Norpseudoephedrine | ND | ND | ND | β-Hydroxyamphetamine | ND | |
| Cathine ((+)-norpseudoephedrine) | 15.0 | 68.3 | >10000 | β-Hydroxyamphetamine | [20] | |
| (–)-Norpseudoephedrine | 30.1 | 294 | >10000 | β-Hydroxyamphetamine | [20] | |
| Racephedrine (racemic ephedrine) | ND | ND | ND | β-Hydroxyamphetamine | ND | |
| Ephedrine ((–)-ephedrine) | 43.1–72.4 | 236–1350 | >10000 | β-Hydroxyamphetamine | [21] | |
| (+)-Ephedrine | 218 | 2104 | >10000 | β-Hydroxyamphetamine | [21][20] | |
| Racemic pseudoephedrine | ND | ND | ND | β-Hydroxyamphetamine | ND | |
| (–)-Pseudoephedrine | 4092 | 9125 | >10000 | β-Hydroxyamphetamine | [20] | |
| Pseudoephedrine ((+)-pseudoephedrine) | 224 | 1988 | >10000 | β-Hydroxyamphetamine | [20] | |
| The smaller the value, the more strongly the substance releases the neurotransmitter. See alsoMonoamine releasing agent § Activity profiles for a larger table with more compounds. | ||||||
[Cathinones] are β-keto analogs of AMPH [...] They can also be viewed as oxidation products of phenylpropanolamines (i.e., β-hydroxyphenylisopropylamines) such as ephedrine and norephedrine. Cathinone is the oxidized version of norephedrine where the β-hydroxyl group of norephedrine has been oxidized to a carbonyl group. [...] Related [phenylisopropylamines] with central stimulant character include β-hydroxyphenylisopropylamines and β-ketophenylisopropylamines. [...] β-hydroxyphenylisopropylamines are more specifically synonymous with phenylpropanolamines, and β-ketophenylisopropylamines are more synonymous with phenylpropanonamines (or, now, more commonly referred to as β-ketoamphetamines, bk-amphetamines, bk-AMPHs, β-keto [phenylisopropylamines], bk-[phenylisopropylamines] or, simply, "synthetic cathinones"). See Fig. 15.1 for structural detail. [...] Figure 15.1 General chemical structures of phenylisopropylamines, phenylpropanolamines, and phenylpropanonamines [...]
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.
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
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