p-Hydroxynorephedrine

p-Hydroxynorephedrine
Clinical data
Other names	4-Hydroxynorephedrine; para-Hydroxynorephedrine
Identifiers
	IUPAC name 4-(2-amino-1-hydroxypropyl)phenol;
JSmol)	Interactive image;
	SMILES NC(C)C(O)c1ccc(O)cc1;
	InChI InChI=1S/C9H13NO2/c1-6(10)9(12)7-2-4-8(11)5-3-7/h2-6,9,11-12H,10H2,1H3; Key:JAYBQRKXEFDRER-UHFFFAOYSA-N;

p-Hydroxynorephedrine (PHN), or 4-hydroxynorephedrine, is the para-hydroxy

p-hydroxyamphetamine and norephedrine.^[2]^[3]^[4]

Amphetamine metabolism

Metabolic pathways of amphetamine in humans^{[sources 1]}

4-Hydroxyphenylacetone

4-Hydroxynorephedrine

DBH
^{[note 1]}

Oxidative
Deamination

In humans, para-hydroxynorephedrine is a metabolite of amphetamine. The

dopamine β-hydroxylase

.

Notes

^ 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.^[6]^[11] 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;^[11]^[13] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.^[14]^[15]

References

^ ^[5]^[6]^[7]^[8]^[9]^[10]^[11]^[12]

References

^ "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Retrieved 30 December 2013.

^
ISBN 9781609133450
. The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.

PMID 4809526
. Retrieved 6 November 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.

PMID 15922018.
Table 5: N-containing drugs and xenobiotics oxygenated by FMO

PMID 10027866
.

PMID 12191709
.

^
PMID 13977820
. Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.

S2CID 23738007
. Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.

S2CID 28641000
. The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).

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.

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.

External links

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

v
t
e
Amphetamine
Main articles
and
pharmaceuticals
Amphetamine

Adzenys ER

Adzenys XR-ODT

Dyanavel XR

Evekeo

Evekeo ODT

Mixed amphetamine salts
Adderall

Adderall XR

Mydayis

Levoamphetamine
N/A
Dextroamphetamine

Dexedrine

ProCentra

Zenzedi

Lisdexamfetamine

Vyvanse

Neuropharmacology
Biomolecular targets

TAAR1 (full agonist)

CART (mRNATooltip messenger RNA inducer)

5-HT1A receptor (low affinity ligand)

MAO (weak competitive inhibitor)

hCA5B, hCA7, hCA12, hCA13, and hCA14 (enzyme activator
)

Inhibited transporters

DAT

NET

SERT

VMAT1

VMAT2

EAAT3

SLC22A3

SLC22A5

Active metabolites

4-Hydroxyamphetamine

4-Hydroxynorephedrine

Norephedrine

Related articles

ADHD

ADHD management

Amphetamine psychosis

Benzedrine in popular culture

Dopamine

Doping in sport

Executive functions

Formetorex

ΔFosB

History and culture of substituted amphetamines

Methamphetamine

Methylphenidate

N-Methylphenethylamine

Motivational salience
Incentive salience

Narcolepsy

Neurobiological effects of physical exercise § Attention deficit hyperactivity disorder

Nootropic

Norepinephrine

Obesity

Performance-enhancing substance

Phenethylamine

Phentermine

Phenylacetone

Recreational drug use

Serotonin

Substituted amphetamine

Trace amine

Category

drug article relating to the nervous system is a stub. You can help Wikipedia by expanding it.
v
t
e

This article about an organic compound is a stub. You can help Wikipedia by expanding it.
v
t
e

[17] 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.^[6]^[11] 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;^[11]^[13] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.^[14]^[15]

[amphetamine_metabolism-13] [5]^[6]^[7]^[8]^[9]^[10]^[11]^[12]

[1] "p-Hydroxynorephedrine". NCBI. PubChem Compound. Retrieved 25 October 2013.

[FDA_side_effects-2] "Adderall XR Prescribing Information" (PDF). Medication Guide. United States Food and Drug Administration. Retrieved 7 October 2013.

[Pubchem_Kinetics-3] "Amphetamine: Biomedical Effects and Toxicity". NCBI. Pubchem Compound. Retrieved 12 October 2013.

[pmid12191709-4] PMID 12191709
.

[FDA_Pharmacokinetics-5] "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Retrieved 30 December 2013.

[Substituted_amphetamines,_FMO,_and_DBH-6] 
ISBN 9781609133450
. The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.

[DBH_amph_primary-7] PMID 4809526
. Retrieved 6 November 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.

[FMO-8] PMID 15922018.
Table 5: N-containing drugs and xenobiotics oxygenated by FMO

[FMO3-Primary-9] PMID 10027866
.

[Metabolites-10] PMID 12191709
.

[pmid13977820-11] 
PMID 13977820
. Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.

[Glycine_conjugation_review-12] S2CID 23738007
. Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.

[DBH_4-HA_primary-14] S2CID 28641000
. The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).

[pmid4457764-15] 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.

[pmid2600821-16] 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.

[2]

[3]

[4]

[sources 1]

[note 1]

[6]

[11]

[13]

[14]

[15]

[5]

[7]

[8]

[9]

[10]

[12]

Amphetamine metabolism

Notes

See also

References

References

External links