4-Hydroxyamphetamine

Hydroxyamphetamine is used in eye drops to dilate the pupil (a process called mydriasis) so that the back of the eye can be examined. This is a diagnostic test for Horner's syndrome. Patients with Horner's syndrome exhibit anisocoria brought about by lesions on the nerves that connect to the nasociliary branch of the ophthalmic nerve.{{cite journal | vauthors = Walton KA, Buono LM | title = Horner syndrome | journal = Current Opinion in Ophthalmology | volume = 14 | issue = 6 | pages = 357–363 | date = December 2003 | pmid = 14615640 | doi = 10.1097/00055735-200312000-00007 | s2cid = 11262166 }} Application of hydroxyamphetamine to the eye can indicate whether the lesion is preganglionic or postganglionic based on the pupil's response. If the pupil dilates, the lesion is preganglionic. If the pupil does not dilate, the lesion is postganglionic.

Hydroxyamphetamine has some limitations to its use as a diagnostic tool. If it is intended as an immediate follow up to another mydriatic drug (cocaine or apraclonidine), then the patient must wait anywhere from a day to a week before hydroxyamphetamine can be administered.{{cite journal | vauthors = Davagnanam I, Fraser CL, Miszkiel K, Daniel CS, Plant GT | title = Adult Horner's syndrome: a combined clinical, pharmacological, and imaging algorithm | journal = Eye | volume = 27 | issue = 3 | pages = 291–298 | date = March 2013 | pmid = 23370415 | pmc = 3597883 | doi = 10.1038/eye.2012.281 }}{{cite journal | vauthors = Lepore FE | title = Diagnostic pharmacology of the pupil | journal = Clinical Neuropharmacology | volume = 8 | issue = 1 | pages = 27–37 | pmid = 3884149 | doi = 10.1097/00002826-198503000-00003 | year = 1985 }} It also has the tendency to falsely localize lesions. False localization can arise in cases of acute onset; in cases where a postganglionic lesion is present, but the nerve still responds to residual norepinephrine; or in cases in which unrelated nerve damage masks the presence of a preganglionic lesion.

Hydroxyamphetamine is a component of two controlled (prescription only), name-brand ophthalmic mydriatics: Paredrine and Paremyd. Paredrine consists of a 1% solution of hydroxyamphetamine hydrobromide{{cite book | vauthors = Slamovits TL, Glaser JS | chapter = The Pupils and Accommodation. | title = Neuro-ophthalmology | veditors = Glaser JS | publisher = Lippincott, Williams, & Wilkins | location = Philadelphia, PA | date = 1999 | isbn = 978-0781717298}}{{rp|543}} while Paremyd consists of a combination of 1% hydroxyamphetamine hydrobromide and 0.25% tropicamide.

Hydroxyamphetamine acts as an indirect sympathomimetic and induces the release of norepinephrine which leads to mydriasis (pupil dilation).

It has also been found to act as a serotonin releasing agent.{{cite journal | vauthors = Nakagawasai O, Arai Y, Satoh SE, Satoh N, Neda M, Hozumi M, Oka R, Hiraga H, Tadano T | title = Monoamine oxidase and head-twitch response in mice. Mechanisms of alpha-methylated substrate derivatives | journal = Neurotoxicology | volume = 25 | issue = 1–2 | pages = 223–232 | date = January 2004 | pmid = 14697897 | doi = 10.1016/S0161-813X(03)00101-3 | bibcode = 2004NeuTx..25..223N | url = }} The drug produces the head-twitch response, a behavioral proxy of psychedelic effects, when it is given by intracerebroventricular injection in animals. This effect is blocked by the serotonin receptor antagonists cyproheptadine and dimethothiazine, by the serotonin reuptake inhibitor fluoxetine, and by the serotonin synthesis inhibitor para-chlorophenylalanine (PCPA). These findings suggest that hydroxyamphetamine-induced head twitches are due to activation of the serotonin 5-HT_2A receptor and that they are mediated by induction of serotonin release as opposed to direct agonism of the serotonin 5-HT_2A receptor. Although hydroxyamphetamine produces the head-twitch response in animals, serotonin releasing agents are not necessarily hallucinogenic in humans, and hence their induction of head twitches in animals has been considered a false positive for psychedelic effects.{{cite book | vauthors = Halberstadt AL, Geyer MA | title=Behavioral Neurobiology of Psychedelic Drugs | chapter=Effect of Hallucinogens on Unconditioned Behavior | veditors = Halberstadt AL, Vollenweider FX, Nichols DE | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | series = Current Topics in Behavioral Neurosciences | volume=36 | date=2018 | isbn=978-3-662-55878-2 | pmid=28224459 | pmc=5787039 | doi=10.1007/7854_2016_466 | doi-access=free | pages=159–199 | quote = Amphetamine and methamphetamine, which act primarily by increasing carrier-mediated release of dopamine and norepinephrine, do not provoke head twitches (Corne and Pickering 1967; Silva and Calil 1975; Yamamoto and Ueki 1975; Jacobs et al. 1976; Bedard and Pycock 1977; Halberstadt and Geyer 2013). By contrast, the 5-HT releasing drugs fenfluramine and p-chloroamphetamine (PCA) do produce a robust HTR (Singleton and Marsden 1981; Darmani 1998a). Fenfluramine and PCA are thought to act indirectly, by increasing carrier-mediated release of 5-HT, because the response can be blocked by inhibition of the 5-HT transporter (Balsara et al. 1986; Darmani 1998a) or by depletion of 5-HT (Singleton and Marsden 1981; Balsara et al. 1986). [...] Because indirect 5-HT agonists such as fenfluramine, PCA, and 5-HTP are not hallucinogenic (Van Praag et al. 1971; Brauer et al. 1996; Turner et al. 2006), their effects on HTR can potentially be classified as false-positive responses.}}{{cite journal | vauthors = Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD | title = Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species | journal = Neuropharmacology | volume = 167 | issue = | pages = 107933 | date = May 2020 | pmid = 31917152 | pmc = 9191653 | doi = 10.1016/j.neuropharm.2019.107933 | url = | quote = Indirect 5-HT2A agonists such as fenfluramine, p-chloroamphetamine (PCA), and 5-hydroxytryptophan (5-HTP) induce head twitches in rodents (Corne et al. 1963; Singleton and Marsden 1981; Darmani 1998) but do not act as hallucinogens in humans (van Praag et al. 1971; Brauer et al. 1996; Turner et al. 2006), However, overdoses of compounds that increase serotonin (5-HT) release can result in 5-HT syndrome, which sometimes includes hallucinations (Birmes et al. 2003; Evans and Sebastian 2007).}}{{cite journal | vauthors = Wojtas A, Gołembiowska K | title = Molecular and Medical Aspects of Psychedelics | journal = Int J Mol Sci | volume = 25 | issue = 1 | date = December 2023 | page = 241 | pmid = 38203411 | pmc = 10778977 | doi = 10.3390/ijms25010241 | doi-access = free | url = | quote = While some false positives have been identified, such as fenfluramine, p-chloroamphetamine, and 5-hydroxytryptophan, the test predominantly exhibits specificity for 5-HT2A receptor agonists [15].}}

It additionally decreases metabolism of serotonin and certain other monoamines by inhibiting the activity of monoamine oxidases (MAOs), particularly type A (MAO-A).{{Citation needed|date=February 2017}} The inhibition of MAO-A prevents metabolism of serotonin and catecholamines in the presynaptic terminal, and thus increases the amount of neurotransmitters available for release into the synaptic cleft.

Like amphetamine, hydroxyamphetamine is an agonist of human TAAR1.{{cite journal | vauthors = Lewin AH, Miller GM, Gilmour B | title = Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class | journal = Bioorganic & Medicinal Chemistry | volume = 19 | issue = 23 | pages = 7044–7048 | date = December 2011 | pmid = 22037049 | pmc = 3236098 | doi = 10.1016/j.bmc.2011.10.007 }}

Hydroxyamphetamine is a major metabolite of amphetamine and a minor metabolite of methamphetamine. In humans, amphetamine is metabolized to hydroxyamphetamine by CYP2D6, which is a member of the cytochrome P450 superfamily and is found in the liver.{{cite journal | vauthors = Markowitz JS, Patrick KS | title = Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder | journal = Clinical Pharmacokinetics | volume = 40 | issue = 10 | pages = 753–772 | pmid = 11707061 | doi = 10.2165/00003088-200140100-00004 | year = 2001 | s2cid = 20884365 }}{{cite journal | vauthors = Haefely W, Bartholini G, Pletscher A | title = Monoaminergic drugs: general pharmacology | journal = Pharmacology & Therapeutics B | volume = 2 | issue = 1 | pages = 185–218 | pmid = 817330 | year = 1976 | doi = 10.1016/0306-039x(76)90030-1 }} 4-Hydroxyamphetamine is then metabolized by dopamine β-hydroxylase into 4-hydroxynorephedrine or eliminated in the urine.{{cite journal | vauthors = Cho AK, Wright J | title = Pathways of metabolism of amphetamine and related compounds | journal = Life Sciences | volume = 22 | issue = 5 | pages = 363–372 | date = February 1978 | pmid = 347211 | doi = 10.1016/0024-3205(78)90282-5 }}

{{Amphetamine pharmacokinetics|caption=In humans, 4-hydroxyamphetamine is formed from CYP2D6 metabolism of amphetamine; 4-hydroxyamphetamine may subsequently be metabolized by dopamine β-hydroxylase into 4-hydroxynorephedrine.}}

Hydroxyamphetamine, also known as 4-hydroxy-α-methylphenethylamine, 4-hydroxyamphetamine, or α-methyltyramine, is a substituted phenethylamine and amphetamine derivative. It is the 4-hydroxylated analogue of amphetamine, the N-demethylated analogue of pholedrine (4-hydroxy-N-methylamphetamine), and the α-methylated analogue of tyramine (4-hydroxyphenethylamine). Other analogues include α-methyldopamine, corbadrine (levonordefrin; α-methylnorepinephrine), and dioxifedrine (α-methylepinephrine).

It has a predicted log P of 0.58 to 1.4.{{cite web | title=4-(2-Aminopropyl)phenol | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/3651 | access-date=30 August 2024}}{{cite web | title=Hydroxyamphetamine: Uses, Interactions, Mechanism of Action | website=DrugBank Online | date=30 January 1992 | url=https://go.drugbank.com/drugs/DB09352 | access-date=30 August 2024}}{{cite web | title=C9H13NO | website=Hydroxyamphetamine | date=30 August 2024 | url=https://www.chemspider.com/Chemical-Structure.3525.html | access-date=30 August 2024}}

Hydroxyamphetamine is used pharmaceutically as the hydrobromide salt.

Hydroxyamphetamine was first synthesized by 1910.

In the 1990s, the trade name rights, patents, and new drug applications (NDAs) for Paredrine and Paremyd were exchanged among a few different manufacturers after a shortage of the raw material required for their production, which caused both drugs to be indefinitely removed from the market.{{cite web | work = Akorn press release | date = March 24, 1999 | url = http://www.thefreelibrary.com/Akorn+Acquires+Paredrine+-+Specialty+Ophthalmic+Diagnostic+Product...-a054197191 | title = Akorn Acquires Paredrine - Specialty Ophthalmic Diagnostic Product From Pharmics, Inc. | access-date = December 9, 2014 | archive-date = September 16, 2018 | archive-url = https://web.archive.org/web/20180916144249/https://www.thefreelibrary.com/Akorn+Acquires+Paredrine+-+Specialty+Ophthalmic+Diagnostic+Product...-a054197191 | url-status = dead }} Around 1997, Akorn, Inc., obtained the rights to both Paredrine and Paremyd,{{cite web | url = http://investors.akorn.com/phoenix.zhtml?c=78132&p=irol-newsArticle&ID=247062 | archive-url = https://archive.today/20141209142458/http://investors.akorn.com/phoenix.zhtml?c=78132&p=irol-newsArticle&ID=247062 | url-status = dead | archive-date = December 9, 2014 | title = Akorn press release }} and in 2002, the company reintroduced Paremyd to the market as a fast acting ophthalmic mydriatic agent.{{cite web | url = http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019261&TABLE1=OB_Rx | title = Hydroxyamphetamine Hydrobromide; Tropicamide | work = Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations | archive-url = https://web.archive.org/web/20160304052043/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019261&TABLE1=OB_Rx | archive-date = 4 March 2016 }}{{cite web | url = http://www.akorn.com/about_timeline.php | title = Akorn timeline | archive-url = https://web.archive.org/web/20190626065749/http://www.akorn.com/about_timeline.php | archive-date=June 26, 2019 | access-date = December 9, 2014 }}{{cite web | vauthors = Lurcott R | work = Ophthalmology Management | date = December 1, 2002 | url = http://www.ophthalmologymanagement.com/articleviewer.aspx?articleID=85623 | title = Unique Mydriatic Returns: The combination formula fosters patient flow efficiencies }}

In 2004, hydroxyamphetamine appeared to remain marketed only in the Czech Republic.

Hydroxyamphetamine is the generic name of the drug and its {{Abbrlink|BAN|British Approved Name}} and {{Abbrlink|DCF|Dénomination Commune Française}}, while hydroxyamfetamine is its {{Abbrlink|INN|International Nonproprietary Name}}.{{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&pg=PA74 | access-date=30 August 2024 | page=74}}{{cite book | vauthors = Morton IK, Hall JM | title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms | publisher=Springer Netherlands | year=2012 | isbn=978-94-011-4439-1 | url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA90 | access-date=30 August 2024 | page=90}}{{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&pg=PA609 | access-date=30 August 2024 | page=609}} In the case of the hydrobromide salt, its generic name is hydroxyamphetamine hydrobromide and this is its {{Abbrlink|USAN|United States Adopted Name}}. It is also known by synonyms including methyltyramine, norpholedrine, and oxamphetamine. The drug is sold under brand names including Paredrine, Paredrinex, Paremyd, Pedrolon, and Mycadrine.

4-Hydroxyamphetamine is also a metabolite of amphetamine and certain other amphetamines.

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• {{MeshName|p-Hydroxyamphetamine}}

{{Amphetamine|state=expanded}}

{{Mydriatics and cycloplegics}}

{{Monoamine releasing agents}}

{{TAAR ligands}}

{{Phenethylamines}}

{{DEFAULTSORT:Hydroxyamphetamine, 4-}}

Category:Abandoned drugs

Category:Amphetamine

Category:Human drug metabolites

Category:Serotonin-norepinephrine-dopamine releasing agents

Category:Ophthalmology drugs

Category:Peripherally selective drugs

Category:4-Hydroxyphenyl compounds

Category:Recreational drug metabolites

Category:Substituted amphetamines

Category:Sympathomimetics

Category:TAAR1 agonists