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Hydroxyamphetamine
INN: Hydroxyamfetamine

Clinical data
Trade names	Paredrine, Paremyd, Pedrolon, Mycadrine, Paredrinex, others
Other names	4-Hydroxyamphetamine; 4-HA; Hydroxyamfetamine; Oxamphetamine; Norpholedrine; para-Hydroxyamphetamine; PHA; α-Methyltyramine; Methyltyramine, Hydroxyamphetamine (USAN US)
Routes of administration	Eye drops
ATC code	None
Legal status
Legal status	In general: ℞ (Prescription only)
Identifiers
IUPAC name 4-(2-aminopropyl)phenol
CAS Number	103-86-6
PubChem CID	3651
ChemSpider	3525
UNII	FQR280JW2N
ChEMBL	ChEMBL1546
CompTox Dashboard (EPA)	DTXSID3023134
ECHA InfoCard	100.002.866
Chemical and physical data
Formula	C9H13NO
Molar mass	151.209 g·mol
3D model (JSmol)	Interactive image
SMILES NC(C)Cc1ccc(O)cc1
InChI InChI=1S/C9H13NO/c1-7(10)6-8-2-4-9(11)5-3-8/h2-5,7,11H,6,10H2,1H3 Key:GIKNHHRFLCDOEU-UHFFFAOYSA-N
(verify)

Hydroxyamphetamine, also known as 4-hydroxyamphetamine or norpholedrine and sold under the brand names Paredrine and Paremyd among others, is a sympathomimetic medication used in eye drops to dilate the pupil for eye examinations.

Hydroxyamfetamine acts as a norepinephrine releasing agent and hence is an indirectly acting sympathomimetic. It is a substituted phenethylamine and amphetamine.

Hydroxyamphetamine appeared to remain marketed only in the Czech Republic as of 2004.

Medical uses

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. 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. 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.

Available forms

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 while Paremyd consists of a combination of 1% hydroxyamphetamine hydrobromide and 0.25% tropicamide.

Pharmacology

Pharmacodynamics

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. 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.

It additionally decreases metabolism of serotonin and certain other monoamines by inhibiting the activity of monoamine oxidases (MAOs), particularly type A (MAO-A). 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.

Pharmacokinetics

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. 4-Hydroxyamphetamine is then metabolized by dopamine β-hydroxylase into 4-hydroxynorephedrine or eliminated in the urine.

Metabolic pathways of amphetamine in humans 4-Hydroxyphenylacetone Phenylacetone Benzoic acid Hippuric acid Amphetamine Norephedrine 4-Hydroxyamphetamine 4-Hydroxynorephedrine Para- Hydroxylation Para- Hydroxylation Para- Hydroxylation CYP2D6 CYP2D6 unidentified Beta- Hydroxylation Beta- Hydroxylation DBH DBH Oxidative Deamination FMO3 Oxidation unidentified Glycine Conjugation XM-ligase GLYAT In humans, 4-hydroxyamphetamine is formed from CYP2D6 metabolism of amphetamine; 4-hydroxyamphetamine may subsequently be metabolized by dopamine β-hydroxylase into 4-hydroxynorephedrine.

Chemistry

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.

Hydroxyamphetamine is used pharmaceutically as the hydrobromide salt.

History

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. Around 1997, Akorn, Inc., obtained the rights to both Paredrine and Paremyd, and in 2002, the company reintroduced Paremyd to the market as a fast acting ophthalmic mydriatic agent.

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

Society and culture

Names

Hydroxyamphetamine is the generic name of the drug and its BANTooltip British Approved Name and DCFTooltip Dénomination Commune Française, while hydroxyamfetamine is its INNTooltip International Nonproprietary Name. In the case of the hydrobromide salt, its generic name is hydroxyamphetamine hydrobromide and this is its USANTooltip 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.

Other drugs

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

Notes

1. 4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo. Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine; however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.

Reference notes

References

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20. Taylor KB (January 1974). "Dopamine-beta-hydroxylase. Stereochemical course of the reaction" (PDF). Journal of Biological Chemistry. 249 (2): 454–458. doi:10.1016/S0021-9258(19)43051-2. PMID 4809526. Retrieved November 6, 2014. Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.
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    Table 5: N-containing drugs and xenobiotics oxygenated by FMO
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27. Freeman JJ, Sulser F (December 1974). "Formation of p-hydroxynorephedrine in brain following intraventricular administration of p-hydroxyamphetamine". Neuropharmacology. 13 (12): 1187–1190. doi:10.1016/0028-3908(74)90069-0. PMID 4457764. In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.
    The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.
28. Matsuda LA, Hanson GR, Gibb JW (December 1989). "Neurochemical effects of amphetamine metabolites on central dopaminergic and serotonergic systems". Journal of Pharmacology and Experimental Therapeutics. 251 (3): 901–908. PMID 2600821. The metabolism of p-OHA to p-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert p-OHA to p-OHNor after intraventricular administration.
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External links

• p-Hydroxyamphetamine at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

• Drugs not assigned an ATC code
• Abandoned drugs
• Amphetamine
• Human drug metabolites
• Serotonin-norepinephrine-dopamine releasing agents
• Ophthalmology drugs
• Peripherally selective drugs
• 4-Hydroxyphenyl compounds
• Recreational drug metabolites
• Substituted amphetamines
• Sympathomimetics
• TAAR1 agonists