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Record Information
Version2.0
Creation Date2009-07-21 20:26:52 UTC
Update Date2014-12-24 20:25:51 UTC
Accession NumberT3D2786
Identification
Common NameMethylphenidate
ClassSmall Molecule
DescriptionMethylphenidate is only found in individuals that have used or taken this drug. It is a central nervous system stimulant used most commonly in the treatment of attention-deficit disorders in children and for narcolepsy. Its mechanisms appear to be similar to those of dextroamphetamine. Methylphenidate blocks dopamine uptake in central adrenergic neurons by blocking dopamine transport or carrier proteins. Methylphenidate acts at the brain stem arousal system and the cerebral cortex and causes increased sympathomimetic activity in the central nervous system. Alteration of serotonergic pathways via changes in dopamine transport may result.
Compound Type
  • Adrenergic Agent
  • Adrenergic Uptake Inhibitor
  • Amine
  • Central Nervous System Stimulant
  • Dopamine Uptake Inhibitor
  • Drug
  • Ester
  • Ether
  • Metabolite
  • Organic Compound
  • Sympathomimetic
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
alpha-Phenyl-2-piperidineacetic acid methyl ester
Concerta
D-Methylphenidate HCl
Daytrana
Equasym XL
Medikinet XL
Metadate
Methyl alpha-phenyl-alpha-(2-piperidyl)acetate
Methyl alpha-phenyl-alpha-2-piperidinylacetate
Methyl phenidyl acetate
Methyl phenidylacetate
Methylin
Methylphenidan
Methylphenidate HCl
Methylphenidate hydrochloride
Methylphenidatum
Methylphenidic acid
Methylphenidylacetate hydrochloride
Metilfenidat hydrochloride
Metilfenidato
MPH
Phenidylate
Quillivant
Quillivant XR
Riphenidate
Ritalin
Rubifen SR
Chemical FormulaC14H19NO2
Average Molecular Mass233.306 g/mol
Monoisotopic Mass233.142 g/mol
CAS Registry Number113-45-1
IUPAC Namemethyl 2-phenyl-2-(piperidin-2-yl)acetate
Traditional Namemethylphenidate
SMILESCOC(=O)C(C1CCCCN1)C1=CC=CC=C1
InChI IdentifierInChI=1/C14H19NO2/c1-17-14(16)13(11-7-3-2-4-8-11)12-9-5-6-10-15-12/h2-4,7-8,12-13,15H,5-6,9-10H2,1H3
InChI KeyInChIKey=DUGOZIWVEXMGBE-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as aralkylamines. These are alkylamines in which the alkyl group is substituted at one carbon atom by an aromatic hydrocarbyl group.
KingdomOrganic compounds
Super ClassOrganic nitrogen compounds
ClassOrganonitrogen compounds
Sub ClassAmines
Direct ParentAralkylamines
Alternative Parents
Substituents
  • Aralkylamine
  • Monocyclic benzene moiety
  • Piperidine
  • Benzenoid
  • Methyl ester
  • Amino acid or derivatives
  • Carboxylic acid ester
  • Carboxylic acid derivative
  • Secondary aliphatic amine
  • Monocarboxylic acid or derivatives
  • Secondary amine
  • Azacycle
  • Organoheterocyclic compound
  • Organopnictogen compound
  • Organooxygen compound
  • Hydrocarbon derivative
  • Carbonyl group
  • Organic oxygen compound
  • Organic oxide
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point224-226°C
Boiling PointNot Available
Solubility1255mg/L
LogP0.2
Predicted Properties
PropertyValueSource
Water Solubility0.18 g/LALOGPS
logP1.47ALOGPS
logP2.25ChemAxon
logS-3.1ALOGPS
pKa (Strongest Basic)9.09ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area38.33 ŲChemAxon
Rotatable Bond Count4ChemAxon
Refractivity66.73 m³·mol⁻¹ChemAxon
Polarizability26.21 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-001i-0090000000-b461cd02e59ebf84d3f9JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-001i-9100000000-c75de12fbdae54dce658JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-001i-0090000000-b461cd02e59ebf84d3f9JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-001i-9100000000-c75de12fbdae54dce658JSpectraViewer | MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0089-9610000000-8e4c1241e36274356032JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-001i-1190000000-8803b6fb1d54baf20a6fJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-001i-6390000000-63f6ddbd32540d6c0e4eJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-001i-9500000000-dab6b5667313005cbcd2JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-001i-0090000000-dbf1d73eb0c9410efbf6JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-001i-2290000000-4a7ee5089439605a9759JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00w9-9520000000-aa484f1df63a11905d5aJSpectraViewer
MSMass Spectrum (Electron Ionization)splash10-001i-9100000000-1a9c5badbee827946da1JSpectraViewer | MoNA
Toxicity Profile
Route of ExposureOral. Readily absorbed in a biphasic manner when orally administered (tablets) to children diagnosed with ADHD and to healthy adults. In children and adults males, after administration of a single oral dose of Ritalin LA and Ritalin given in two doses 4 hours apart, peak plasma concentration is reached approximately 2 hours for the first phase and 5-6 hours for the second phase. The absolute oral bioavailability of methylphenidate in children was 22±8% for d-methylphenidate and 5±3% for l-methylphenidate. These low values suggest that methylphenidate is highly metabolized presystemically.
Mechanism of ToxicityMethylphenidate blocks dopamine uptake in central adrenergic neurons by blocking dopamine transport or carrier proteins. Methylphenidate acts at the brain stem arousal system and the cerebral cortex and causes increased sympathomimetic activity in the central nervous system. Alteration of serotonergic pathways via changes in dopamine transport may result.
MetabolismMethylphenidate is hepatically metabolized. More specifically, it is rapidly and extensively metabolized by carboxylesterase CES1A1. Via this enzyme, methylphenidate undergoes de-esterification to ritalinic acid (a-phenyl-2-piperidine acetic acid, PPAA), which has little to no pharmacologic activity. Route of Elimination: After oral administration of an immediate release formulation of methylphenidate, 78%-97% of the dose is excreted in the urine and 1%-3% in the feces in the form of metabolites within 48-96 hours. Only small quantities (<1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as ritalinic acid (60%-86%), the remainder being accounted for by minor metabolites. Half Life: d-methylphenidate = 3-4 hours; l-methylphenidate = 1-3 hours; Ritalinic acid = 3-4 hours;
Toxicity ValuesLD50: 190 mg/kg (oral, mice)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor use as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity.
Minimum Risk LevelNot Available
Health EffectsUsing large amounts of these drugs can result in a condition known as amphetamine psychosis -- which can result in auditory, visual and tactile hallucinations, intense paranoia, irrational thoughts and beliefs, delusions, and mental confusion.
SymptomsSymptoms of overdose include vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.
TreatmentTreatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage. In the presence of severe intoxication, use a carefully titrated dosage of a short-acting barbiturate before performing gastric lavage. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia. (8)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00422
HMDB IDHMDB14566
PubChem Compound ID4158
ChEMBL IDCHEMBL796
ChemSpider ID4015
KEGG IDC07196
UniProt IDNot Available
OMIM ID
ChEBI ID6887
BioCyc IDNot Available
CTD IDNot Available
Stitch IDMethylphenidate
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkMethylphenidate
References
Synthesis Reference

DrugSyn.org

MSDST3D2786.pdf
General References
  1. Fone KC, Nutt DJ: Stimulants: use and abuse in the treatment of attention deficit hyperactivity disorder. Curr Opin Pharmacol. 2005 Feb;5(1):87-93. [15661631 ]
  2. Keating GM, McClellan K, Jarvis B: Methylphenidate (OROS formulation). CNS Drugs. 2001;15(6):495-500; discussion 501-3. [11524026 ]
  3. Markowitz JS, DeVane CL, Pestreich LK, Patrick KS, Muniz R: A comprehensive in vitro screening of d-, l-, and dl-threo-methylphenidate: an exploratory study. J Child Adolesc Psychopharmacol. 2006 Dec;16(6):687-98. [17201613 ]
  4. Sharma RP, Javaid JI, Pandey GN, Easton M, Davis JM: Pharmacological effects of methylphenidate on plasma homovanillic acid and growth hormone. Psychiatry Res. 1990 Apr;32(1):9-17. [2190251 ]
  5. Shults T, Kownacki AA, Woods WE, Valentine R, Dougherty J, Tobin T: Pharmacokinetics and behavioral effects of methylphenidate in Thoroughbred horses. Am J Vet Res. 1981 May;42(5):722-6. [7258793 ]
  6. FDA label
  7. Drugs.com [Link]
  8. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated GenesNot Available

Targets

General Function:
Monoamine transmembrane transporter activity
Specific Function:
Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name:
SLC6A3
Uniprot ID:
Q01959
Molecular Weight:
68494.255 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.11 uMNot AvailableBindingDB 50062912
IC500.017 uMNot AvailableBindingDB 50062912
IC500.079 uMNot AvailableBindingDB 50062912
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Dresel SH, Kung MP, Huang X, Plossl K, Hou C, Shiue CY, Karp J, Kung HF: In vivo imaging of serotonin transporters with [99mTc]TRODAT-1 in nonhuman primates. Eur J Nucl Med. 1999 Apr;26(4):342-7. [10199939 ]
  3. Izenwasser S, Coy AE, Ladenheim B, Loeloff RJ, Cadet JL, French D: Chronic methylphenidate alters locomotor activity and dopamine transporters differently from cocaine. Eur J Pharmacol. 1999 Jun 4;373(2-3):187-93. [10414438 ]
  4. Volkow ND, Fowler JS, Gatley SJ, Dewey SL, Wang GJ, Logan J, Ding YS, Franceschi D, Gifford A, Morgan A, Pappas N, King P: Comparable changes in synaptic dopamine induced by methylphenidate and by cocaine in the baboon brain. Synapse. 1999 Jan;31(1):59-66. [10025684 ]
  5. Wayment HK, Deutsch H, Schweri MM, Schenk JO: Effects of methylphenidate analogues on phenethylamine substrates for the striatal dopamine transporter: potential as amphetamine antagonists? J Neurochem. 1999 Mar;72(3):1266-74. [10037500 ]
  6. Volkow ND, Wang GJ, Fowler JS, Fischman M, Foltin R, Abumrad NN, Gatley SJ, Logan J, Wong C, Gifford A, Ding YS, Hitzemann R, Pappas N: Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain. Life Sci. 1999;65(1):PL7-12. [10403500 ]
  7. Meltzer PC, Wang P, Blundell P, Madras BK: Synthesis and evaluation of dopamine and serotonin transporter inhibition by oxacyclic and carbacyclic analogues of methylphenidate. J Med Chem. 2003 Apr 10;46(8):1538-45. [12672255 ]
  8. Froimowitz M, Gu Y, Dakin LA, Nagafuji PM, Kelley CJ, Parrish D, Deschamps JR, Janowsky A: Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter. J Med Chem. 2007 Jan 25;50(2):219-32. [17228864 ]
General Function:
Norepinephrine:sodium symporter activity
Specific Function:
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name:
SLC6A2
Uniprot ID:
P23975
Molecular Weight:
69331.42 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.66 uMNot AvailableBindingDB 50062912
IC500.061 uMNot AvailableBindingDB 50062912
References
  1. Yang L, Wang YF, Li J, Faraone SV: Association of norepinephrine transporter gene with methylphenidate response. J Am Acad Child Adolesc Psychiatry. 2004 Sep;43(9):1154-8. [15322419 ]
  2. Williard RL, Middaugh LD, Zhu HJ, Patrick KS: Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity. Behav Pharmacol. 2007 Feb;18(1):39-51. [17218796 ]
  3. Chuhan YS, Taukulis HK: Impairment of single-trial memory formation by oral methylphenidate in the rat. Neurobiol Learn Mem. 2006 Mar;85(2):125-31. Epub 2005 Oct 24. [16246598 ]
  4. Gray JD, Punsoni M, Tabori NE, Melton JT, Fanslow V, Ward MJ, Zupan B, Menzer D, Rice J, Drake CT, Romeo RD, Brake WG, Torres-Reveron A, Milner TA: Methylphenidate administration to juvenile rats alters brain areas involved in cognition, motivated behaviors, appetite, and stress. J Neurosci. 2007 Jul 4;27(27):7196-207. [17611273 ]
  5. Sandoval V, Riddle EL, Ugarte YV, Hanson GR, Fleckenstein AE: Methamphetamine-induced rapid and reversible changes in dopamine transporter function: an in vitro model. J Neurosci. 2001 Feb 15;21(4):1413-9. [11160413 ]
  6. Froimowitz M, Gu Y, Dakin LA, Nagafuji PM, Kelley CJ, Parrish D, Deschamps JR, Janowsky A: Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter. J Med Chem. 2007 Jan 25;50(2):219-32. [17228864 ]
General Function:
Serotonin:sodium symporter activity
Specific Function:
Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner.
Gene Name:
SLC6A4
Uniprot ID:
P31645
Molecular Weight:
70324.165 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory65 uMNot AvailableBindingDB 50062912
IC505.1 uMNot AvailableBindingDB 50062912
References
  1. Dresel SH, Kung MP, Huang X, Plossl K, Hou C, Shiue CY, Karp J, Kung HF: In vivo imaging of serotonin transporters with [99mTc]TRODAT-1 in nonhuman primates. Eur J Nucl Med. 1999 Apr;26(4):342-7. [10199939 ]
  2. Izenwasser S, Coy AE, Ladenheim B, Loeloff RJ, Cadet JL, French D: Chronic methylphenidate alters locomotor activity and dopamine transporters differently from cocaine. Eur J Pharmacol. 1999 Jun 4;373(2-3):187-93. [10414438 ]
  3. Stehouwer JS, Jarkas N, Zeng F, Voll RJ, Williams L, Owens MJ, Votaw JR, Goodman MM: Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. J Med Chem. 2006 Nov 16;49(23):6760-7. [17154506 ]
  4. Froimowitz M, Gu Y, Dakin LA, Nagafuji PM, Kelley CJ, Parrish D, Deschamps JR, Janowsky A: Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter. J Med Chem. 2007 Jan 25;50(2):219-32. [17228864 ]