Substituted β-hydroxyamphetamine

{{Short description|Class of compounds based upon the β-hydroxyamphetamine structure}}

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{{Redirect|β-Hydroxyamphetamines|the chemical|β-Hydroxyamphetamine||Hydroxyamphetamine}}

{{Infobox drug class

| Name = Substituted β-hydroxyamphetamines

| Image = File:Norephedrin.svg

| ImageClass = skin-invert-image

| Width = 150px

| Alt = Racemic β-hydroxyamphetamine skeleton

| Caption = Racemic β-hydroxyamphetamine skeleton

| Synonyms = β-Hydroxyamphetamines; β-Hydroxyphenylisopropylamines; β-Hydroxyphenylaminopropanes; Phenylisopropanolamines; Phenylpropanolamines; Norephedrines; Amphetanolamines; Cathinols; Cathines

| Chemical_class = Substituted derivatives of β-hydroxyamphetamine

}}

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.{{cite journal | vauthors = Glennon RA | title = Bath salts, mephedrone, and methylenedioxypyrovalerone as emerging illicit drugs that will need targeted therapeutic intervention | journal = Adv Pharmacol | volume = 69 | issue = | pages = 581–620 | date = 2014 | pmid = 24484988 | pmc = 4471862 | doi = 10.1016/B978-0-12-420118-7.00015-9 | url = | quote=[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 [...] }}{{cite book | vauthors = Elks J | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer US | year=2014 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ | access-date=30 August 2024 }}{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum: International Drug Directory | publisher=Medpharm Scientific Publishers | year=2004 | isbn=978-3-88763-101-7 | url=https://books.google.com/books?id=EgeuA47Ocm4C | access-date=30 August 2024}}{{cite journal | vauthors = McCreary AC, Müller CP, Filip M | title = Psychostimulants: Basic and Clinical Pharmacology | journal = International Review of Neurobiology | volume = 120 | issue = | pages = 41–83 | date = 2015 | pmid = 26070753 | doi = 10.1016/bs.irn.2015.02.008 }}{{cite journal | vauthors = Oosterbaan R, Burns MJ | title = Myocardial infarction associated with phenylpropanolamine | journal = The Journal of Emergency Medicine | volume = 18 | issue = 1 | pages = 55–59 | date = January 2000 | pmid = 10645839 | doi = 10.1016/s0736-4679(99)00176-6 | quote = 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. }} They are substituted phenethylamines, phenylethanolamines (β-hydroxyphenethylamines), and amphetamines (α-methylphenethylamines), and are closely related to but distinct from the substituted cathinones (β-ketoamphetamines).{{cite journal | vauthors = Nadal-Gratacós N, Pazos MD, Pubill D, Camarasa J, Escubedo E, Berzosa X, López-Arnau R | title=Structure–Activity Relationship of Synthetic Cathinones: An Updated Review | journal=ACS Pharmacology & Translational Science | date=6 August 2024 | issn=2575-9108 | doi=10.1021/acsptsci.4c00299 | quote=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| doi-access=free }} 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.{{cite journal | vauthors = Rothman RB, Baumann MH | title = Targeted screening for biogenic amine transporters: potential applications for natural products | journal = Life Sciences | volume = 78 | issue = 5 | pages = 512–518 | date = December 2005 | pmid = 16202429 | doi = 10.1016/j.lfs.2005.09.001 }}{{cite journal | vauthors = Docherty JR | title = Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA) | journal = British Journal of Pharmacology | volume = 154 | issue = 3 | pages = 606–622 | date = June 2008 | pmid = 18500382 | pmc = 2439527 | doi = 10.1038/bjp.2008.124 }}{{cite journal | vauthors = Cheshire WP | title = Chemical pharmacotherapy for the treatment of orthostatic hypotension | journal = Expert Opinion on Pharmacotherapy | volume = 20 | issue = 2 | pages = 187–199 | date = February 2019 | pmid = 30376728 | doi = 10.1080/14656566.2018.1543404 }} In contrast to their amphetamine counterparts, ephedrine and 4-fluoroephedrine are not agonists of the human trace amine-associated receptor 1 (TAAR1).{{cite journal | vauthors = Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME | title = In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1 | journal = J Pharmacol Exp Ther | volume = 357 | issue = 1 | pages = 134–144 | date = April 2016 | pmid = 26791601 | doi = 10.1124/jpet.115.229765 | url = }} 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.{{cite journal | vauthors = O'Donnell SR | title = Sympathomimetic vasoconstrictors as nasal decongestants | journal = The Medical Journal of Australia | volume = 162 | issue = 5 | pages = 264–267 | date = March 1995 | pmid = 7534374 | doi = 10.5694/j.1326-5377.1995.tb139882.x }}{{cite journal | vauthors = Bouchard R, Weber AR, Geiger JD | title = Informed decision-making on sympathomimetic use in sport and health | journal = Clinical Journal of Sport Medicine | volume = 12 | issue = 4 | pages = 209–224 | date = July 2002 | pmid = 12131054 | doi = 10.1097/00042752-200207000-00003 }} For comparison, the predicted log P (XLogP3) of amphetamine is 1.8,{{cite web | title=Amphetamine | work = PubChem | publisher = U.S. National Library of Medicine | url=https://pubchem.ncbi.nlm.nih.gov/compound/3007 | access-date=2 September 2024}} of β-hydroxyamphetamine is 0.8,{{cite web | title=2-Amino-1-phenyl-1-propanol | work = PubChem | publisher = U.S. National Library of Medicine | url=https://pubchem.ncbi.nlm.nih.gov/compound/4786 | access-date=2 September 2024}} and of cathinone is 1.1.{{cite web | title=Cathinone | work = PubChem | publisher = U.S. National Library of Medicine | url=https://pubchem.ncbi.nlm.nih.gov/compound/62258 | access-date=2 September 2024}} 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.{{cite journal | vauthors = Bharate SS, Mignani S, Vishwakarma RA | title = Why Are the Majority of Active Compounds in the CNS Domain Natural Products? A Critical Analysis | journal = Journal of Medicinal Chemistry | volume = 61 | issue = 23 | pages = 10345–10374 | date = December 2018 | pmid = 29989814 | doi = 10.1021/acs.jmedchem.7b01922 }}{{cite journal | vauthors = Pajouhesh H, Lenz GR | title = Medicinal chemical properties of successful central nervous system drugs | journal = NeuroRx | volume = 2 | issue = 4 | pages = 541–553 | date = October 2005 | pmid = 16489364 | pmc = 1201314 | doi = 10.1602/neurorx.2.4.541 | quote = 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 }} 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.