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Phenylalanine
Phenylalanine
(symbol Phe or F[2]) is an α-amino acid with the formula C 9H 11NO 2. It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino acid is classified as neutral, and nonpolar because of the inert and hydrophobic nature of the benzyl side chain. The L-isomer is used to biochemically form proteins, coded for by DNA. The codons for L-phenylalanine are UUU and UUC. Phenylalanine
Phenylalanine
is a precursor for tyrosine, the monoamine neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), and the skin pigment melanin. Phenylalanine
Phenylalanine
is found naturally in the breast milk of mammals. It is used in the manufacture of food and drink products and sold as a nutritional supplement for its reputed analgesic and antidepressant effects. It is a direct precursor to the neuromodulator phenethylamine, a commonly used dietary supplement. As an essential amino acid, phenylalanine is not synthesized de novo in humans and other animals, who must ingest phenylalanine or phenylalanine-containing proteins.

Contents

1 History 2 Dietary sources 3 Dietary recommendations 4 Other biological roles

4.1 In plants

5 Phenylketonuria 6 D-, L- and DL-phenylalanine 7 Commercial synthesis 8 Derivatives 9 References 10 External links

History[edit] The first description of phenylalanine was made in 1879, when Schulze and Barbieri identified a compound with the empirical formula, C9H11NO2, in yellow lupine (Lupinus luteus) seedlings. In 1882, Erlenmeyer and Lipp first synthesized phenylalanine from phenylacetaldehyde, hydrogen cyanide, and ammonia.[3][4] The genetic codon for phenylalanine was first discovered by J. Heinrich Matthaei and Marshall W. Nirenberg
Marshall W. Nirenberg
in 1961. They showed that by using mRNA to insert multiple uracil repeats into the genome of the bacterium E. coli, they could cause the bacterium to produce a polypeptide consisting solely of repeated phenylalanine amino acids. This discovery helped to establish the nature of the coding relationship that links information stored in genomic nucleic acid with protein expression in the living cell. Dietary sources[edit] Good sources of phenylalanine are eggs, chicken, liver, beef, milk, and soybeans.[5] Dietary recommendations[edit] The Food and Nutrition Board (FNB) of the U.S. Institute of Medicine set Recommended Dietary Allowances (RDAs) for essential amino acids in 2002. For phenylalanine plus tyrosine, for adults 19 years and older, 33 mg/kg body weight/day.[6] Other biological roles[edit] L-Phenylalanine
L-Phenylalanine
is biologically converted into L-tyrosine, another one of the DNA-encoded amino acids. L-tyrosine in turn is converted into L-DOPA, which is further converted into dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). The latter three are known as the catecholamines. Phenylalanine
Phenylalanine
uses the same active transport channel as tryptophan to cross the blood–brain barrier. In excessive quantities, supplementation can interfere with the production of serotonin and other aromatic amino acids as well as nitric oxide due to the overuse (eventually, limited availability) of the associated cofactors, iron or tetrahydrobiopterin.[medical citation needed] The corresponding enzymes in for those compounds are the aromatic amino acid hydroxylase family and nitric oxide synthase.

Biosynthetic pathways for catecholamines and trace amines in the human brain[7][8][9]

L-Phenylalanine L-Tyrosine L-DOPA Epinephrine Phenethylamine p-Tyramine Dopamine Norepinephrine N-Methylphenethylamine N-Methyltyramine p-Octopamine Synephrine 3-Methoxytyramine AADC AADC AADC primary pathway PNMT PNMT PNMT PNMT AAAH AAAH brain CYP2D6 minor pathway COMT DBH DBH

Phenylalanine
Phenylalanine
in humans may ultimately be metabolized into a range of different substances.

In plants[edit] Phenylalanine
Phenylalanine
is the starting compound used in the synthesis of flavonoids. Lignan
Lignan
is derived from phenylalanine and from tyrosine. Phenylalanine
Phenylalanine
is converted to cinnamic acid by the enzyme phenylalanine ammonia-lyase.[10] Phenylketonuria[edit] Main article: Phenylketonuria The genetic disorder phenylketonuria (PKU) is the inability to metabolize phenylalanine because of a lack of the enzyme phenylalanine hydroxylase. Individuals with this disorder are known as "phenylketonurics" and must regulate their intake of phenylalanine. Phenylketonurics often use blood tests to monitor the amount of phenylalanine in their blood. Lab results may report phenylalanine levels using either mg/dL and μmol/L. One mg/dL of phenylalanine is approximately equivalent to 60 μmol/L. A (rare) "variant form" of phenylketonuria called hyperphenylalaninemia is caused by the inability to synthesize a cofactor called tetrahydrobiopterin, which can be supplemented. Pregnant women with hyperphenylalaninemia may show similar symptoms of the disorder (high levels of phenylalanine in blood) but these indicators will usually disappear at the end of gestation. Pregnant women with PKU must control their blood phenylalanine levels even if the fetus is heterozygous for the defective gene because the fetus could be adversely affected due to hepatic immaturity.[medical citation needed] A non-food source of phenylalanine is the artificial sweetener aspartame. This compound is metabolized by the body into several chemical byproducts including phenylalanine. The breakdown problems phenylketonurics have with the buildup of phenylalanine in the body also occurs with the ingestion of aspartame, although to a lesser degree. Accordingly, all products in Australia, the U.S. and Canada that contain aspartame must be labeled: "Phenylketonurics: Contains phenylalanine." In the UK, foods containing aspartame must carry ingredient panels that refer to the presence of "aspartame or E951"[11] and they must be labeled with a warning "Contains a source of phenylalanine." In Brazil, the label "Contém Fenilalanina" (Portuguese for "Contains Phenylalanine") is also mandatory in products which contain it. These warnings are placed to help individuals avoid such foods. Geneticists have recently sequenced the genome of macaques. Their investigations have found "some instances where the normal form of the macaque protein looks like the diseased human protein" including markers for PKU.[12] D-, L- and DL-phenylalanine[edit] The stereoisomer D-phenylalanine (DPA) can be produced by conventional organic synthesis, either as a single enantiomer or as a component of the racemic mixture. It does not participate in protein biosynthesis although it is found in proteins in small amounts - particularly aged proteins and food proteins that have been processed. The biological functions of D-amino acids
D-amino acids
remain unclear, although D-phenylalanine has pharmacological activity at niacin receptor 2.[13] D L-Phenylalanine
L-Phenylalanine
(DLPA) is marketed as a nutritional supplement for its purported analgesic and antidepressant activities. D L-Phenylalanine
L-Phenylalanine
is a mixture of D-phenylalanine and L-phenylalanine. The reputed analgesic activity of DL-phenylalanine may be explained by the possible blockage by D-phenylalanine of enkephalin degradation by the enzyme carboxypeptidase A.[14] The mechanism of DL-phenylalanine's supposed antidepressant activity may be accounted for by the precursor role of L-phenylalanine in the synthesis of the neurotransmitters norepinephrine and dopamine. Elevated brain levels of norepinephrine and dopamine are thought to have an antidepressant effect. D- Phenylalanine
Phenylalanine
is absorbed from the small intestine and transported to the liver via the portal circulation. A small amount of D-phenylalanine appears to be converted to L-phenylalanine. D- Phenylalanine
Phenylalanine
is distributed to the various tissues of the body via the systemic circulation. It appears to cross the blood–brain barrier less efficiently than L-phenylalanine, and so a small amount of an ingested dose of D-phenylalanine is excreted in the urine without penetrating the central nervous system.[citation needed] L-Phenylalanine
L-Phenylalanine
is an antagonist at α2δ Ca2+ calcium channels with a Ki of 980 nM.[15] In the brain, L-phenylalanine is a competitive antagonist at the glycine binding site of NMDA receptor[16] and at the glutamate binding site of AMPA receptor.[17] At the glycine binding site of NMDA receptor L-phenylalanine has an apparent equilibrium dissociation constant (KB) of 573 µM estimated by Schild regression[18] which is considerably lower than brain L-phenylalanine concentration observed in untreated human phenylketonuria.[19] L-Phenylalanine
L-Phenylalanine
also inhibits neurotransmitter release at glutamatergic synapses in hippocampus and cortex with IC50
IC50
of 980 µM, a brain concentration seen in classical phenylketonuria, whereas D-phenylalanine has a significantly smaller effect.[17] Commercial synthesis[edit] L-Phenylalanine
L-Phenylalanine
is produced for medical, feed, and nutritional applications, such as aspartame, in large quantities by utilizing the bacterium Escherichia coli, which naturally produces aromatic amino acids like phenylalanine. The quantity of L-phenylalanine produced commercially has been increased by genetically engineering E. coli, such as by altering the regulatory promoters or amplifying the number of genes controlling enzymes responsible for the synthesis of the amino acid.[20] Derivatives[edit] Boronophenylalanine (BPA) is a dihydroxyboryl derivative of phenylalanine, used in neutron capture therapy. References[edit]

^ Dawson RM, et al. (1959). Data for Biochemical Research. Oxford: Clarendon Press.  ^ "Nomenclature and Symbolism for Amino Acids and Peptides". IUPAC-IUB Joint Commission on Biochemical Nomenclature. 1983. Archived from the original on 9 October 2008. Retrieved 5 March 2018.  ^ Thorpe TE (1913). A Dictionary of Applied Chemistry. Longmans, Green, and Co. pp. 191–193. Retrieved 2012-06-04.  ^ Plimmer RH (1912) [1908]. Plimmer RH, Hopkins FG, eds. The Chemical Composition of the Proteins. Monographs on Biochemistry. Part I. Analysis (2nd ed.). London: Longmans, Green and Co. pp. 93–97. Retrieved 2012-06-04.  ^ Ross HM, Roth J (1 April 1991). The Mood Control Diet: 21 Days to Conquering Depression and Fatigue. Simon & Schuster. p. 59. ISBN 978-0-13-590449-7.  ^ Institute of Medicine
Institute of Medicine
(2002). " Protein
Protein
and Amino Acids". Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC: The National Academies Press. pp. 589–768.  ^ Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186.  ^ Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID 15860375.  ^ Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". Eur. J. Pharmacol. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199.  ^ Nelson DL, Cox MM (2000). Lehninger, Principles of Biochemistry (3rd ed.). New York: Worth Publishing. ISBN 1-57259-153-6.  ^ "Aspartame". UK: Food Standards Agency.  ^ Gibbs RA, Rogers J, Katze MG, Bumgarner R, Weinstock GM, Mardis ER, et al. (April 2007). "Evolutionary and biomedical insights from the rhesus macaque genome". Science (pdf)format= requires url= (help). 316 (5822): 222–34. doi:10.1126/science.1139247. PMID 17431167.  ^ "D-phenylalanine". IUPHAR. Retrieved 24 June 2014.  ^ Christianson DW, Mangani S, Shoham G, Lipscomb WN (August 1989). "Binding of D-phenylalanine and D-tyrosine to carboxypeptidase A" (pdf). The Journal of Biological Chemistry. 264 (22): 12849–53. PMID 2568989.  ^ Mortell KH, Anderson DJ, Lynch JJ, Nelson SL, Sarris K, McDonald H, Sabet R, Baker S, Honore P, Lee CH, Jarvis MF, Gopalakrishnan M (March 2006). "Structure-activity relationships of alpha-amino acid ligands for the alpha2delta subunit of voltage-gated calcium channels". Bioorganic & Medicinal Chemistry Letters. 16 (5): 1138–41. doi:10.1016/j.bmcl.2005.11.108. PMID 16380257.  ^ Glushakov AV, Dennis DM, Morey TE, Sumners C, Cucchiara RF, Seubert CN, Martynyuk AE (2002). "Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria". Molecular Psychiatry. 7 (4): 359–67. doi:10.1038/sj.mp.4000976. PMID 11986979.  ^ a b Glushakov AV, Dennis DM, Sumners C, Seubert CN, Martynyuk AE (April 2003). "L-phenylalanine selectively depresses currents at glutamatergic excitatory synapses". Journal of Neuroscience Research. 72 (1): 116–24. doi:10.1002/jnr.10569. PMID 12645085.  ^ Glushakov AV, Glushakova O, Varshney M, Bajpai LK, Sumners C, Laipis PJ, Embury JE, Baker SP, Otero DH, Dennis DM, Seubert CN, Martynyuk AE (February 2005). "Long-term changes in glutamatergic synaptic transmission in phenylketonuria". Brain. 128 (Pt 2): 300–7. doi:10.1093/brain/awh354. PMID 15634735.  ^ Möller HE, Weglage J, Bick U, Wiedermann D, Feldmann R, Ullrich K (December 2003). "Brain imaging and proton magnetic resonance spectroscopy in patients with phenylketonuria". Pediatrics. 112 (6 Pt 2): 1580–3. PMID 14654669.  ^ Sprenger GA (2007). "Aromatic Amino Acids". Amino Acid Biosynthesis: Pathways, Regulation and Metabolic Engineering (1st ed.). Springer. pp. 106–113. ISBN 978-3-540-48595-7. 

External links[edit]

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Phenylalanine
Phenylalanine
mass spectrum Phenylalanine
Phenylalanine
at ChemSynthesis

v t e

The encoded amino acid

General topics

Protein Peptide Genetic code

By properties

Aliphatic

Branched-chain amino acids (Valine Isoleucine Leucine) Methionine Alanine Proline Glycine

Aromatic

Phenylalanine Tyrosine Tryptophan Histidine

Polar, uncharged

Asparagine Glutamine Serine Threonine

Positive charge (pKa)

Lysine
Lysine
(≈10.8) Arginine
Arginine
(≈12.5) Histidine
Histidine
(≈6.1)

Negative charge (pKa)

Aspartic acid
Aspartic acid
(≈3.9) Glutamic acid
Glutamic acid
(≈4.1) Cysteine
Cysteine
(≈8.3) Tyrosine
Tyrosine
(≈10.1)

Amino acids
Amino acids
types: Encoded (proteins) Essential Non-proteinogenic Ketogenic Glucogenic Imino acids D-amino acids Dehydroamino acids

v t e

Amino acid
Amino acid
metabolism metabolic intermediates

K→acetyl-CoA

lysine→

Saccharopine Allysine α-Aminoadipic acid α-Ketoadipate Glutaryl-CoA Glutaconyl-CoA Crotonyl-CoA β-Hydroxybutyryl-CoA

leucine→

β-Hydroxy β-methylbutyric acid β-Hydroxy β-methylbutyryl-CoA Isovaleryl-CoA α-Ketoisocaproic acid β-Ketoisocaproic acid β-Ketoisocaproyl-CoA β-Leucine β-Methylcrotonyl-CoA β-Methylglutaconyl-CoA β-Hydroxy β-methylglutaryl-CoA

tryptophan→alanine→

N'-Formylkynurenine Kynurenine Anthranilic acid 3-Hydroxykynurenine 3-Hydroxyanthranilic acid 2-Amino-3-carboxymuconic semialdehyde 2-Aminomuconic semialdehyde 2-Aminomuconic acid Glutaryl-CoA

G

G→pyruvate→citrate

glycine→serine→

3-Phosphoglyceric acid

glycine→creatine: Glycocyamine Phosphocreatine Creatinine

G→glutamate→ α-ketoglutarate

histidine→

Urocanic acid Imidazol-4-one-5-propionic acid Formiminoglutamic acid Glutamate-1-semialdehyde

proline→

1-Pyrroline-5-carboxylic acid

arginine→

Agmatine Ornithine Citrulline Cadaverine Putrescine

other

cysteine+glutamate→glutathione: γ-Glutamylcysteine

G→propionyl-CoA→ succinyl-CoA

valine→

α-Ketoisovaleric acid Isobutyryl-CoA Methacrylyl-CoA 3-Hydroxyisobutyryl-CoA 3-Hydroxyisobutyric acid 2-Methyl-3-oxopropanoic acid

isoleucine→

2,3-Dihydroxy-3-methylpentanoic acid 2-Methylbutyryl-CoA Tiglyl-CoA 2-Methylacetoacetyl-CoA

methionine→

generation of homocysteine: S-Adenosyl methionine S-Adenosyl-L-homocysteine Homocysteine

conversion to cysteine: Cystathionine alpha-Ketobutyric acid+Cysteine

threonine→

α-Ketobutyric acid

propionyl-CoA→

Methylmalonyl-CoA

G→fumarate

phenylalanine→tyrosine→

4-Hydroxyphenylpyruvic acid Homogentisic acid 4-Maleylacetoacetic acid

G→oxaloacetate

see urea cycle

Other

Cysteine
Cysteine
metabolism

Cysteine
Cysteine
sulfinic acid

v t e

Dopamine
Dopamine
receptor modulators

D1-like

Agonists

Benzazepines: 6-Br-APB Fenoldopam SKF-38,393 SKF-77,434 SKF-81,297 SKF-82,958 SKF-83,959 Trepipam Zelandopam

Ergolines: Cabergoline CY-208,243 Dihydroergocryptine LEK-8829 Lisuride Pergolide Terguride

Dihydrexidine
Dihydrexidine
derivatives: A-77636 A-86929 Adrogolide
Adrogolide
(ABT-431, DAS-431) Dihydrexidine Dinapsoline Dinoxyline Doxanthrine

Phenethylamines: BCO-001 Deoxyepinephrine
Deoxyepinephrine
(N-methyldopamine, epinine) Dopexamine Etilevodopa Ibopamine L-DOPA
L-DOPA
(levodopa) Melevodopa L-Phenylalanine L-Tyrosine XP21279

Others: A-68930 Apomorphine Isocorypalmine Nuciferine PF-6649751 PF 6669571 Propylnorapomorphine Rotigotine SKF-89,145 SKF-89,626 Stepholidine Tetrahydropalmatine

Antagonists

Typical antipsychotics: Butaclamol Chlorpromazine Chlorprothixene Flupentixol
Flupentixol
(flupenthixol) (+melitracen) Fluphenazine Loxapine Perphenazine
Perphenazine
(+amitriptyline) Pifluthixol Thioridazine Thiothixene Trifluoperazine
Trifluoperazine
(+tranylcypromine) Zuclopenthixol

Atypical antipsychotics: Asenapine Clorotepine Clotiapine Clozapine DHA-clozapine Fluperlapine Iloperidone Norclozapine Norquetiapine Olanzapine
Olanzapine
(++fluoxetine) Paliperidone Quetiapine Risperidone Tefludazine Zicronapine Ziprasidone Zotepine

Others: Berupipam Ecopipam EEDQ Metitepine
Metitepine
(methiothepin) Odapipam Perlapine SCH-23390

D2-like

Agonists

Adamantanes: Amantadine Memantine Rimantadine

Aminotetralins: 5-OH-DPAT 7-OH-DPAT 8-OH-PBZI Rotigotine UH-232

Ergolines: Bromocriptine Cabergoline Dihydroergocryptine Epicriptine Ergocornine Lisuride LSD Pergolide Terguride

Dihydrexidine
Dihydrexidine
derivatives: 2-OH-NPA Ciladopa Dihydrexidine Dinoxyline N,N-Propyldihydrexidine

Phenethylamines: Deoxyepinephrine
Deoxyepinephrine
(N-methyldopamine, epinine) Dopexamine Etilevodopa Ibopamine L-DOPA
L-DOPA
(levodopa) L-Phenylalanine L-Tyrosine Melevodopa XP21279

Atypical antipsychotics: Alentemol
Alentemol
(U-66444B) Aripiprazole
Aripiprazole
(+sertraline) Aripiprazole
Aripiprazole
lauroxil Bifeprunox Brexpiprazole Cariprazine F-15063 Lumateperone Norclozapine RP-5063

Others: 3-PPP A-412997 ABT-670 ABT-724 Adrafinil Aplindore Apomorphine Arketamine Armodafinil BP-897 Captodiame CP-226,269 Dizocilpine Esketamine Flibanserin GSK-789,472 Ketamine Mesulergine Modafinil OSU-6162 Pardoprunox PD-128,907 PD-168,077 PF-219,061 PF-592,379 Phencyclidine Piribedil Pramipexole Preclamol Propylnorapomorphine Pukateine Quinagolide Quinelorane Quinpirole RDS-127 Ro10-5824 Ropinirole Roxindole Salvinorin A SKF-83,959 Sumanirole Talipexole Umespirone WAY-100,635

Antagonists

Typical antipsychotics: Acepromazine Acetophenazine Azaperone Benperidol Bromperidol Butaclamol Butaperazine Chloracizine Chlorproethazine Chlorpromazine Chlorprothixene Ciclindole Clopenthixol Clothixamide Clopimozide Droperidol Fluacizine Fluanisone Flucindole Fluotracen Flupentixol
Flupentixol
(flupenthixol) (+melitracen) Fluphenazine Fluprothixene Fluspirilene Haloperidol Homopipramol Lenperone Levomepromazine
Levomepromazine
(methotrimeprazine) Levosulpiride Loxapine Mesoridazine Moperone Naranol Nemonapride Penfluridol Perathiepin Perazine Pericyazine (periciazine) Perphenazine
Perphenazine
(+amitriptyline) Piflutixol (pifluthixol) Pimozide Pipamperone Preclamol Prochlorperazine Promazine Prothipendyl Spiperone
Spiperone
(spiroperidol) Sulforidazine Sulpiride Sultopride Teflutixol Thiopropazate Thioproperazine Thioridazine Thiothixene Timiperone Trifluoperazine
Trifluoperazine
(+tranylcypromine) Triflupromazine Trifluperidol Zetidoline Zuclopenthixol

Atypical antipsychotics: Amisulpride Asenapine BL-1020 Blonanserin Carpipramine Cinuperone Clocapramine Clorotepine Clotiapine
Clotiapine
(clothiapine) Clozapine Cyamemazine DHA-clozapine Dixyrazine Elopiprazole Flumezapine Fluperlapine Gevotroline Iloperidone Lurasidone Mazapertine Melperone Molindone Mosapramine Ocaperidone Olanzapine
Olanzapine
(+fluoxetine) Paliperidone Perospirone Piperacetazine Pipotiazine Piquindone Quetiapine Remoxipride Risperidone Sertindole Tefludazine Tenilapine Tiospirone Veralipride Zicronapine Ziprasidone Zotepine

Antiemetics/gastroprokinetics/sedatives: Aceprometazine AS-8112 Alimemazine Alizapride Benzquinamide Bromopride Clebopride Domperidone Eticlopride Hydroxyzine Itopride Metoclopramide Metopimazine Promethazine Thiethylperazine Trimethobenzamide

Antidepressants: Amoxapine Nefazodone Opipramol Propiomazine Trimipramine

Others: 3-PPP Alpiropride Azapride Buspirone Desmethoxyfallypride EEDQ F-15063 Fallypride Fananserin Fenfluramine GSK-789,472 Iodobenzamide Isocorypalmine L-741,626 L-745,870 Levofenfluramine LEK-8829 Metergoline Metitepine
Metitepine
(methiothepin) N-Methylspiperone Nafadotride Nuciferine PNU-99,194 Pridopidine Raclopride Sarizotan SB-277,011-A Seridopidine Sonepiprazole Spiroxatrine Stepholidine SV-293 Tetrahydropalmatine Tiapride UH-232 Yohimbine

See also: Receptor/signaling modulators Adrenergics Serotonergics Monoamine reuptake inhibitors Monoamine releasing agents Monoamine metabolism modulators Monoamine neurotoxins

v t e

Opioid receptor
Opioid receptor
modulators

MOR

Agonists (abridged; see here for a full list): 3-HO-PCP 7-Acetoxymitragynine 7-Hydroxymitragynine ψ-Akuammigine α-Chlornaltrexamine α-Narcotine Acetyldihydrocodeine Acetylfentanyl Acrylfentanyl Adrenorphin
Adrenorphin
(metorphamide) AH-7921 Akuammicine Akuammidine Alfentanil Anileridine Apparicine β-Endorphin BAM-12P BAM-18P BAM-22P Benzhydrocodone Benzylmorphine Bezitramide Biphalin BU08070 Buprenorphine Butorphan Butorphanol Butyrfentanyl BW-373U86 Carfentanil Casokefamide Cebranopadol Chloroxymorphamine Codeine DADLE DAMGO
DAMGO
(DAGO) Dermorphin Desmetramadol
Desmetramadol
(desmethyltramadol) Desomorphine Dextromoramide Dextropropoxyphene
Dextropropoxyphene
(propoxyphene) Dezocine Dimenoxadol Dimethylaminopivalophenone Eluxadoline Diamorphine (heroin) Dihydrocodeine Dihydroetorphine Dihydromorphine Diphenoxylate Dipipanone Dynorphin A Embutramide Endomorphin-1 Endomorphin-2 Eseroline Ethylmorphine Etorphine Fentanyl Fluorophen Frakefamide Furanylfentanyl Hemorphin-4 Herkinorin Hodgkinsine Hydrocodone Hydromorphinol Hydromorphone IBNtxA Ketamine Ketobemidone Kratom Laudanosine Lefetamine Leu-enkephalin Levacetylmethadol Levomethorphan Levorphanol Lexanopadol Loperamide Loxicodegol Matrine Meptazinol Met-enkephalin
Met-enkephalin
(metenkefalin) Methadone Metkefamide Metopon Mitragynine Mitragynine
Mitragynine
pseudoindoxyl Morphiceptin Morphine Nalbuphine Nalbuphine
Nalbuphine
sebacate NalBzOH Nalmexone Naltalimide Neopine NFEPP Nicocodeine Nicodicodeine Nicomorphine NKTR-181 Norketamine Octreotide Oliceridine OM-3-MNZ Oripavine Oxycodone Oxymorphazone Oxymorphonazine Oxymorphone Oxymorphone
Oxymorphone
phenylhydrazone OxyPNPH Papaver somniferum
Papaver somniferum
(opium) Pentazocine Pericine Pethidine
Pethidine
(meperidine) Phenazocine Phencyclidine Piminodine Piritramide PL-017 Prodine Propiram PZM21 Racemethorphan Racemorphan Remifentanil Salsolinol SC-17599 Sinomenine Sufentanil Tapentadol Tetrahydropapaveroline TH-030418 Thebaine Thienorphine Tianeptine Tilidine Tramadol Trimebutine TRIMU 5 TRV734 Tubotaiwine U-47700 Valorphin Viminol Xorphanol

PAMs: BMS-986121 BMS-986122

Antagonists: (3S,4S)-Picenadol 2-(S)-N,N-(R)-Viminol 3CS-nalmefene 4-Caffeoyl-1,5-quinide 4′-Hydroxyflavanone 4',7-Dihydroxyflavone 6β-Naltrexol 6β-Naltrexol-d4 18-MC α-Gliadin β-Chlornaltrexamine β-Funaltrexamine Akuammine Alvimopan AM-251 Apigenin AT-076 Axelopran Bevenopran Catechin Catechin
Catechin
gallate Clocinnamox CTAP CTOP Cyclofoxy Cyprodime Diacetylnalorphine Diprenorphine ECG EGC Epicatechin Eptazocine Gemazocine Ginsenoside R Hyperoside Ibogaine Levallorphan Lobeline LY-255582 LY-2196044 Methocinnamox Methylnaltrexone Methylsamidorphan chloride Naldemedine Nalmefene Nalodeine
Nalodeine
(N-allylnorcodeine) Nalorphine Nalorphine
Nalorphine
dinicotinate Naloxazone Naloxegol Naloxol Naloxonazine Naloxone Naltrexazone Naltrexonazine Naltrexone Naltrindole Naringenin Noribogaine Oxilorphan Pawhuskin A Rimonabant Quadazocine Samidorphan Taxifolin

Unknown/unsorted: Cannabidiol Coronaridine Cyproterone acetate Dihydroakuuamine Tabernanthine Tetrahydrocannabinol

DOR

Agonists: 3CS-nalmefene 6'-GNTI 7-SIOM ADL-5747 (PF-04856881) ADL-5859 Alazocine
Alazocine
(SKF-10047) Amoxapine AR-M100390 (ARM390) AZD2327 β-Endorphin BAM-18P Biphalin BU-48 Butorphan Butorphanol BW-373U86 Casokefamide Cebranopadol Codeine Cyclazocine DADLE Deltorphin
Deltorphin
A Deltorphin
Deltorphin
I Deltorphin
Deltorphin
II Desmethylclozapine Desmetramadol
Desmetramadol
(desmethyltramadol) Dezocine Diamorphine (heroin) Dihydroetorphine Dihydromorphine DPDPE DPI-221 DPI-3290 DSLET Ethylketazocine Etorphine Fentanyl FIT Fluorophen Hemorphin-4 Hydrocodone Hydromorphone Ibogaine Isomethadone JNJ-20788560 KNT-127 Kratom Laudanosine Leu-enkephalin Levomethorphan Levorphanol Lexanopadol Lofentanil Met-enkephalin
Met-enkephalin
(metenkefalin) Metazocine Metkefamide Mitragynine Mitragynine
Mitragynine
pseudoindoxyl Morphine N-Phenethyl-14-ethoxymetopon Norbuprenorphine NalBzOH Oripavine Oxycodone Oxymorphone Pethidine
Pethidine
(meperidine) Proglumide Racemethorphan Racemorphan RWJ-394674 Samidorphan SB-235863 SNC-80 SNC-162 TAN-67
TAN-67
(SB-205,607) TH-030418 Thebaine Thiobromadol
Thiobromadol
(C-8813) Tonazocine Tramadol TRV250 Xorphanol Zenazocine

Antagonists: 4',7-Dihydroxyflavone 5'-NTII 6β-Naltrexol 6β-Naltrexol-d4 α-Santolol β-Chlornaltrexamine Apigenin AT-076 Axelopran Bevenopran BNTX Catechin Catechin
Catechin
gallate Clocinnamox Diacetylnalorphine Diprenorphine ECG EGC Eluxadoline Epicatechin ICI-154129 ICI-174864 LY-255582 LY-2196044 Methylnaltrexone Methylnaltrindole N-Benzylnaltrindole Nalmefene Nalorphine Naltrexone Naltriben Naltrindole Naloxone Naringenin Noribogaine Pawhuskin A Quadazocine SDM25N SoRI-9409 Taxifolin Thienorphine

Unknown/unsorted: 18-MC Cannabidiol Coronaridine Cyproterone acetate Tabernanthine Tetrahydrocannabinol

KOR

Agonists: 3CS-nalmefene 6'-GNTI 8-CAC 18-MC 14-Methoxymetopon β-Chlornaltrexamine β-Funaltrexamine Adrenorphin
Adrenorphin
(metorphamide) Akuuamicine Alazocine
Alazocine
(SKF-10047) Allomatrine Apadoline Asimadoline BAM-12P BAM-18P BAM-22P Big dynorphin Bremazocine BRL-52537 Butorphan Butorphanol BW-373U86 Cebranopadol Ciprefadol CR665 Cyclazocine Cyclorphan Cyprenorphine Desmetramadol
Desmetramadol
(desmethyltramadol) Diamorphine (heroin) Diacetylnalorphine Difelikefalin Dihydroetorphine Dihydromorphine Diprenorphine Dynorphin A Dynorphin B
Dynorphin B
(rimorphin) Eluxadoline Enadoline Eptazocine Erinacine E Ethylketazocine Etorphine Fedotozine Fentanyl Gemazocine GR-89696 GR-103545 Hemorphin-4 Herkinorin HS665 Hydromorphone HZ-2 Ibogaine ICI-199,441 ICI-204,448 Ketamine Ketazocine Laudanosine Leumorphin (dynorphin B-29) Levallorphan Levomethorphan Levorphanol Lexanopadol Lofentanil LPK-26 Lufuradom Matrine MB-1C-OH Menthol Metazocine Metkefamide Mianserin Mirtazapine Morphine Moxazocine MR-2034 N-MPPP Nalbuphine Nalbuphine
Nalbuphine
sebacate NalBzOH Nalfurafine Nalmefene Nalodeine
Nalodeine
(N-allylnorcodeine) Nalorphine Naltriben Niravoline Norbuprenorphine Norbuprenorphine-3-glucuronide Noribogaine Norketamine Oripavine Oxilorphan Oxycodone Pentazocine Pethidine
Pethidine
(meperidine) Phenazocine Proxorphan Racemethorphan Racemorphan RB-64 Salvinorin A
Salvinorin A
(salvia) Salvinorin B ethoxymethyl ether Salvinorin B methoxymethyl ether Samidorphan Spiradoline
Spiradoline
(U-62,066) TH-030418 Thienorphine Tifluadom Tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline) U-50,488 U-54,494A U-69,593 Xorphanol

Antagonists: 4′-Hydroxyflavanone 4',7-Dihydroxyflavone 5'-GNTI 6'-GNTI 6β-Naltrexol 6β-Naltrexol-d4 β-Chlornaltrexamine Buprenorphine/samidorphan Amentoflavone ANTI Apigenin Arodyne AT-076 Axelopran AZ-MTAB Binaltorphimine BU09059 Buprenorphine Catechin Catechin
Catechin
gallate CERC-501
CERC-501
(LY-2456302) Clocinnamox Cyclofoxy Dezocine DIPPA EGC ECG Epicatechin Hyperoside JDTic LY-255582 LY-2196044 LY-2444296 LY-2459989 LY-2795050 MeJDTic Methylnaltrexone ML190 ML350 MR-2266 N-Fluoropropyl-JDTic Naloxone Naltrexone Naltrindole Naringenin Norbinaltorphimine Noribogaine Pawhuskin A PF-4455242 RB-64 Quadazocine Taxifolin UPHIT Zyklophin

Unknown/unsorted: Akuammicine Akuammine Coronaridine Cyproterone acetate Dihydroakuuamine Ibogamine Tabernanthine

NOP

Agonists: (Arg14,Lys15)Nociceptin ((pF)Phe4)Nociceptin(1-13)NH2 (Phe1Ψ(CH2-NH)Gly2)Nociceptin(1-13)NH2 Ac-RYYRWK-NH2 Ac-RYYRIK-NH2 BU08070 Buprenorphine Cebranopadol Dihydroetorphine Etorphine JNJ-19385899 Levomethorphan Levorphanol Levorphanol Lexanopadol MCOPPB MT-7716 NNC 63-0532 Nociceptin
Nociceptin
(orphanin FQ) Nociceptin
Nociceptin
(1-11) Nociceptin
Nociceptin
(1-13)NH2 Norbuprenorphine Racemethorphan Racemorphan Ro64-6198 Ro65-6570 SCH-221510 SCH-486757 SR-8993 SR-16435 TH-030418

Antagonists: (Nphe1)Nociceptin(1-13)NH2 AT-076 BAN-ORL-24 BTRX-246040
BTRX-246040
(LY-2940094) J-113397 JTC-801 NalBzOH Nociceptin
Nociceptin
(1-7) Nocistatin SB-612111 SR-16430 Thienorphine Trap-101 UFP-101

Unsorted

β-Casomorphins Amidorphin BAM-20P Cytochrophin-4 Deprolorphin Gliadorphin
Gliadorphin
(gluteomorphin) Gluten exorphins Hemorphins Kava
Kava
constituents MEAGL MEAP NEM Neoendorphins Nepetalactone
Nepetalactone
(catnip) Peptide
Peptide
B Peptide
Peptide
E Peptide
Peptide
F Peptide
Peptide
I Rubiscolins Soymorphins

Others

Enkephalinase inhibitors: Amastatin BL-2401 Candoxatril D -Phenylalanine Dexecadotril (retorphan) Ecadotril
Ecadotril
(sinorphan) Kelatorphan Racecadotril
Racecadotril
(acetorphan) RB-101 RB-120 RB-3007 Opiorphan Selank Semax Spinorphin Thiorphan Tynorphin Ubenimex
Ubenimex
(bestatin)

Propeptides: β-Lipotropin (proendorphin) Prodynorphin Proenkephalin Pronociceptin Proopiomelanocortin
Proopiomelanocortin
(POMC)

Others: Kyotorphin
Kyotorphin
(met-enkephalin releaser/degradation stabilizer)

See also: Receptor/signaling modulators • Signaling peptide/protein receptor modulators

v t e

Phenethylamines

Phenethylamines

Psychedelics: 25B-NBOMe 25C-NBOMe 25D-NBOMe 25I-NBOMe 25N-NBOMe

2C-B 2C-B-AN 2C-Bn 2C-Bu 2C-C 2C-CN 2C-CP 2C-D 2C-E 2C-EF 2C-F 2C-G 2C-G-1 2C-G-2 2C-G-3 2C-G-4 2C-G-5 2C-G-6 2C-G-N 2C-H 2C-I 2C-iP 2C-N 2C-NH2 2C-O 2C-O-4 2C-P 2C-Ph 2C-SE 2C-T 2C-T-2 2C-T-3 2C-T-4 2C-T-5 2C-T-6 2C-T-7 2C-T-8 2C-T-9 2C-T-10 2C-T-11 2C-T-12 2C-T-13 2C-T-14 2C-T-15 2C-T-16 2C-T-17 2C-T-18 2C-T-19 2C-T-20 2C-T-21 2C-T-22 2C-T-22.5 2C-T-23 2C-T-24 2C-T-25 2C-T-27 2C-T-28 2C-T-30 2C-T-31 2C-T-32 2C-T-33 2C-TFE 2C-TFM 2C-YN 2C-V

Allylescaline DESOXY Escaline Isoproscaline Jimscaline Macromerine MEPEA Mescaline Metaescaline Methallylescaline Proscaline Psi-2C-T-4 TCB-2 Stimulants: Phenylethanolamine Hordenine Phenethylamine α-Methylphenethylamine (amphetamine) β-Methylphenethylamine m-Methylphenethylamine N-Methylphenethylamine o-Methylphenethylamine p-Methylphenethylamine

Entactogens: Lophophine MDPEA MDMPEA Others: BOH DMPEA

Amphetamines

Psychedelics: 3C-BZ 3C-E 3C-P Aleph Beatrice Bromo-DragonFLY D-Deprenyl DMA DMCPA DMMDA DOB DOC DOEF DOET DOI DOM DON DOPR DOTFM Ganesha MMDA MMDA-2 Psi-DOM TMA TeMA Stimulants: 2-FA 2-FMA 3-FA 3-FMA Acridorex Alfetamine Amfecloral Amfepentorex Amphetamine
Amphetamine
(Dextroamphetamine, Levoamphetamine) Amphetaminil Benfluorex Benzphetamine Cathine Clobenzorex Dimethylamphetamine Ephedrine Etilamfetamine Fencamfamin Fencamine Fenethylline Fenfluramine
Fenfluramine
(Dexfenfluramine, Levofenfluramine) Fenproporex Flucetorex Fludorex Formetorex Furfenorex Gepefrine 4-Hydroxyamphetamine Iofetamine Isopropylamphetamine Lefetamine Lisdexamfetamine Mefenorex Metaraminol Methamphetamine
Methamphetamine
(Dextromethamphetamine, Levomethamphetamine) Methoxyphenamine MMA Morforex Norfenfluramine L -Norpseudoephedrine N,alpha-Diethylphenylethylamine Oxifentorex Oxilofrine Ortetamine PBA PCA Phenpromethamine PFA PFMA PIA PMA PMEA PMMA Phenylpropanolamine Pholedrine Prenylamine Propylamphetamine Pseudoephedrine Sibutramine Tiflorex Tranylcypromine Xylopropamine Zylofuramine Entactogens: 4-FA 4-FMA 4-MA 4-MMA 4-MTA 5-APB 5-APDB 5-EAPB 5-IT 5-MAPB 5-MAPDB 6-APB 6-APDB 6-Chloro-MDMA 6-EAPB 6-IT 6-MAPB 6-MAPDB EDA IAP 2,3-MDA 3,4-MDA (tenamfetamine) MDEA MDHMA MDMA
MDMA
(midomafetamine) MDOH Methamnetamine MMDMA Naphthylaminopropane TAP Others: 3,4-DCA Amiflamine DiFMDA Selegiline
Selegiline
(also D -Deprenyl)

Phentermines

Stimulants: Chlorphentermine Cloforex Clortermine Etolorex Mephentermine Pentorex Phentermine Entactogens: MDPH MDMPH Others: Cericlamine

Cathinones

Stimulants: 3-FMC 4-MC 4-BMC 4-CMC 4-EMC 4-FMC 4-MEC 4-MeMABP 4-MPD Amfepramone Benzedrone Brephedrone Buphedrone Bupropion Cathinone Dimethylcathinone Ethcathinone Eutylone Hydroxybupropion Methcathinone Methedrone NEB Pentedrone Pentylone Radafaxine Entactogens: 3,4-DMMC 3-MMC Butylone Ethylone Methylone Methylenedioxycathinone Mephedrone

Phenylisobutylamines

Entactogens: 4-CAB 4-MAB Ariadne BDB Butylone EBDB Eutylone MBDB Stimulants: Phenylisobutylamine

Phenylalkylpyrrolidines

Stimulants: α-PBP α-PHP α-PPP α-PVP MDPBP MDPPP MDPV 4-MePBP 4-MePHP 4-MePPP MOPPP MOPVP MPBP MPHP MPPP Naphyrone PEP Prolintane Pyrovalerone

Catecholamines (and close relatives)

6-FNE 6-OHDA a-Me-DA a-Me-TRA Adrenochrome Ciladopa D -DOPA (Dextrodopa) Dimetofrine Dopamine Epinephrine Epinine Etilefrine Ethylnorepinephrine Fenclonine Ibopamine Isoprenaline Isoetarine L -DOPA (Levodopa) L -DOPS (Droxidopa) L -Phenylalanine L -Tyrosine m-Tyramine Metanephrine Metaraminol Metaterol Metirosine Methyldopa N,N-Dimethyldopamine Nordefrin
Nordefrin
(Levonordefrin) Norepinephrine Norfenefrine
Norfenefrine
(m-Octopamine) Normetanephrine Orciprenaline p-Octopamine p-Tyramine Phenylephrine Synephrine

Miscellaneous

AL-LAD Amidephrine Arbutamine Cafedrine Denopamine Desvenlafaxine Diphenidine Dizocilpine Dobutamine Dopexamine Ephenidine Etafedrine ETH-LAD Famprofazone Fluorolintane Hexapradol IP-LAD Lysergic acid amide Lysergic acid 2-butyl amide Lysergic acid 2,4-dimethylazetidide Lysergic acid diethylamide Methoxamine Methoxphenidine MT-45 PARGY-LAD Phenibut PRO-LAD Pronethalol Salbutamol
Salbutamol
(Levosalbutamol) Solriamfetol Theodrenaline Thi

.