Substituted β-hydroxyamphetamines, or simply 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 | β-Hydroxyamphetamines; 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
edit- ^ a b c d e f Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. ISBN 978-1-4757-2085-3. Retrieved 30 August 2024.
- ^ a b c d e f Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. ISBN 978-3-88763-101-7. Retrieved 30 August 2024.
- ^ a b c McCreary AC, Müller CP, Filip M (2015). "Psychostimulants: Basic and Clinical Pharmacology". International Review of Neurobiology. 120: 41–83. doi:10.1016/bs.irn.2015.02.008. PMID 26070753.
- ^ Oosterbaan R, Burns MJ (January 2000). "Myocardial infarction associated with phenylpropanolamine". The Journal of Emergency Medicine. 18 (1): 55–59. doi:10.1016/s0736-4679(99)00176-6. PMID 10645839.
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.
- ^ Nadal-Gratacós N, Pazos MD, Pubill D, Camarasa J, Escubedo E, Berzosa X, et al. (6 August 2024). "Structure–Activity Relationship of Synthetic Cathinones: An Updated Review". ACS Pharmacology & Translational Science. doi:10.1021/acsptsci.4c00299. ISSN 2575-9108.
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
- ^ a b c Rothman RB, Baumann MH (2003). "Monoamine transporters and psychostimulant drugs". Eur. J. Pharmacol. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135.
- ^ Rothman RB, Baumann MH (December 2005). "Targeted screening for biogenic amine transporters: potential applications for natural products". Life Sciences. 78 (5): 512–518. doi:10.1016/j.lfs.2005.09.001. PMID 16202429.
- ^ a b c Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Curr Top Med Chem. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID 17017961.
- ^ a b Docherty JR (June 2008). "Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)". British Journal of Pharmacology. 154 (3): 606–622. doi:10.1038/bjp.2008.124. PMC 2439527. PMID 18500382.
- ^ a b Cheshire WP (February 2019). "Chemical pharmacotherapy for the treatment of orthostatic hypotension". Expert Opinion on Pharmacotherapy. 20 (2): 187–199. doi:10.1080/14656566.2018.1543404. PMID 30376728.
- ^ Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME (April 2016). "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther. 357 (1): 134–144. doi:10.1124/jpet.115.229765. PMID 26791601.
- ^ a b c O'Donnell SR (March 1995). "Sympathomimetic vasoconstrictors as nasal decongestants". The Medical Journal of Australia. 162 (5): 264–267. doi:10.5694/j.1326-5377.1995.tb139882.x. PMID 7534374.
- ^ a b c Bouchard R, Weber AR, Geiger JD (July 2002). "Informed decision-making on sympathomimetic use in sport and health". Clinical Journal of Sport Medicine. 12 (4): 209–224. doi:10.1097/00042752-200207000-00003. PMID 12131054.
- ^ "Amphetamine". PubChem. U.S. National Library of Medicine. Retrieved 2 September 2024.
- ^ "2-Amino-1-phenyl-1-propanol". PubChem. U.S. National Library of Medicine. Retrieved 2 September 2024.
- ^ "Cathinone". PubChem. U.S. National Library of Medicine. Retrieved 2 September 2024.
- ^ a b Bharate SS, Mignani S, Vishwakarma RA (December 2018). "Why Are the Majority of Active Compounds in the CNS Domain Natural Products? A Critical Analysis". Journal of Medicinal Chemistry. 61 (23): 10345–10374. doi:10.1021/acs.jmedchem.7b01922. PMID 29989814.
- ^ a b Pajouhesh H, Lenz GR (October 2005). "Medicinal chemical properties of successful central nervous system drugs". NeuroRx. 2 (4): 541–553. doi:10.1602/neurorx.2.4.541. PMC 1201314. PMID 16489364.
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
- ^ a b c d e f g h i j Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, et al. (October 2003). "In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates". J Pharmacol Exp Ther. 307 (1): 138–145. doi:10.1124/jpet.103.053975. PMID 12954796.
- ^ a b c d e f Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707.
- ^ Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, et al. (2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–562. doi:10.1038/npp.2012.204. PMC 3572453. PMID 23072836.
- ^ Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, et al. (April 2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–203. doi:10.1038/npp.2011.304. PMC 3306880. PMID 22169943.