Basic Info

Common NameCodeine(F04746)
2D Structure
Description

In the United States, codeine is regulated by the Controlled Substances Act. It is a Schedule II controlled substance for pain-relief products containing codeine alone. In combination with aspirin or acetaminophen (paracetamol/tylenol) it is listed as Schedule III. Codeine is also available outside the United States as an over-the-counter drug (Schedule V) in liquid cough-relief formulations. Internationally, codeine is a Schedule II drug under the Single Convention on Narcotic Drugs. In the United Kingdom, codeine is regulated by the Misuse of Drugs Act 1971; it is a Class B Drug, except for concentrations of less than 8mg when combined with paracetamol - or 12.5mg when combined with ibuprofen - which are available in many over the counter preparations. it is a Class B Drug, except for concentrations of less than 8mg when combined with paracetamol - or 12.5mg when combined with ibuprofen - which are available in many over the counter preparations. An opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough. Codeine or methylmorphine is an opiate used for its analgesic, antitussive and antidiarrheal properties. It is marketed as the salts codeine sulfate and codeine phosphate. Codeine hydrochloride is more commonly marketed in contintental Europe and other regions. Codeine is an alkaloid found in opium in concentrations ranging from 0.3 to 3.0 percent. While codeine can be extracted from opium, most codeine is synthesized from morphine through the process of O-methylation. In the United Kingdom, codeine is regulated by the Misuse of Drugs Act 1971; Codeine or methylmorphine is an opiate used for its analgesic, antitussive and antidiarrheal properties. It is marketed as the salts codeine sulfate and codeine phosphate. Codeine hydrochloride is more commonly marketed in contintental Europe and other regions. Codeine is an alkaloid found in opium in concentrations ranging from 0.3 to 3.0 percent. While codeine can be extracted from opium, most codeine is synthesized from morphine through the process of O-methylation. Theoretically, a dose of approximately 200 mg (oral) of codeine must be administered to give equivalent analgesia to 30 mg (oral) of morphine (Rossi, 2004). It is not used, however, in single doses of greater than 60mg (and no more than 240 mg in 24 hours) since there is a ceiling effect. [PubChem]Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Codeine's analgesic activity is, most likely, due to its conversion to morphine. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.

FRCD IDF04746
CAS Number76-57-3
PubChem CID5284371
FormulaC18H21NO3
IUPAC Name

(4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol

InChI Key

OROGSEYTTFOCAN-DNJOTXNNSA-N

InChI

InChI=1S/C18H21NO3/c1-19-8-7-18-11-4-5-13(20)17(18)22-16-14(21-2)6-3-10(15(16)18)9-12(11)19/h3-6,11-13,17,20H,7-9H2,1-2H3/t11-,12+,13-,17-,18-/m0/s1

Canonical SMILES

CN1CCC23C4C1CC5=C2C(=C(C=C5)OC)OC3C(C=C4)O

Isomeric SMILES

CN1CC[C@]23[C@@H]4[C@H]1CC5=C2C(=C(C=C5)OC)O[C@H]3[C@H](C=C4)O

WikipediaCodeine
Synonyms
        
            codeine
        
            Methylmorphine
        
            Codeine anhydrous
        
            Codicept
        
            l-Codeine
        
            Coducept
        
            Morphine monomethyl ether
        
            Morphine 3-methyl ether
        
            (-)-Codeine
        
            76-57-3
        
Classifies
                

                  
                    Predicted: Pollutant
                  

                
        
Update DateNov 13, 2018 17:07

Chemical Taxonomy

KingdomOrganic compounds
SuperclassAlkaloids and derivatives
ClassMorphinans
SubclassNot available
Intermediate Tree NodesNot available
Direct ParentMorphinans
Alternative Parents
Molecular FrameworkAromatic heteropolycyclic compounds
SubstituentsMorphinan - Phenanthrene - Tetralin - Coumaran - Anisole - Alkyl aryl ether - Aralkylamine - Piperidine - Benzenoid - Secondary alcohol - Tertiary amine - Tertiary aliphatic amine - Oxacycle - Ether - Azacycle - Organoheterocyclic compound - Organic nitrogen compound - Alcohol - Hydrocarbon derivative - Organooxygen compound - Organonitrogen compound - Organopnictogen compound - Organic oxygen compound - Amine - Aromatic heteropolycyclic compound
DescriptionThis compound belongs to the class of organic compounds known as morphinans. These are polycyclic compounds with a four-ring skeleton with three condensed six-member rings forming a partially hydrogenated phenanthrene moiety, one of which is aromatic while the two others are alicyclic.

Properties

Property NameProperty Value
Molecular Weight299.37
Hydrogen Bond Donor Count1
Hydrogen Bond Acceptor Count4
Rotatable Bond Count1
Complexity509
Monoisotopic Mass299.152
Exact Mass299.152
XLogP1.1
Formal Charge0
Heavy Atom Count22
Defined Atom Stereocenter Count5
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Isotope Atom Count0
Covalently-Bonded Unit Count1

ADMET

Model Result Probability
Absorption
Blood-Brain BarrierBBB+0.9979
Human Intestinal AbsorptionHIA+0.9966
Caco-2 PermeabilityCaco2+0.8867
P-glycoprotein SubstrateSubstrate0.8631
P-glycoprotein InhibitorInhibitor0.5435
Non-inhibitor0.8724
Renal Organic Cation TransporterInhibitor0.6380
Distribution
Subcellular localizationMitochondria0.4895
Metabolism
CYP450 2C9 SubstrateNon-substrate0.7698
CYP450 2D6 SubstrateSubstrate0.9274
CYP450 3A4 SubstrateSubstrate0.7796
CYP450 1A2 InhibitorNon-inhibitor0.6494
CYP450 2C9 InhibitorNon-inhibitor0.8866
CYP450 2D6 InhibitorInhibitor0.6978
CYP450 2C19 InhibitorNon-inhibitor0.8256
CYP450 3A4 InhibitorNon-inhibitor0.8899
CYP Inhibitory PromiscuityLow CYP Inhibitory Promiscuity0.7470
Excretion
Toxicity
Human Ether-a-go-go-Related Gene InhibitionWeak inhibitor0.8556
Non-inhibitor0.8615
AMES ToxicityNon AMES toxic0.9133
CarcinogensNon-carcinogens0.9567
Fish ToxicityHigh FHMT0.8941
Tetrahymena Pyriformis ToxicityHigh TPT0.8916
Honey Bee ToxicityLow HBT0.5107
BiodegradationNot ready biodegradable0.9935
Acute Oral ToxicityII0.7450
Carcinogenicity (Three-class)Non-required0.7141

Model Value Unit
Absorption
Aqueous solubility-2.0336LogS
Caco-2 Permeability1.5243LogPapp, cm/s
Distribution
Metabolism
Excretion
Toxicity
Rat Acute Toxicity2.8450LD50, mol/kg
Fish Toxicity0.7325pLC50, mg/L
Tetrahymena Pyriformis Toxicity0.8107pIGC50, ug/L

References

TitleJournalDatePubmed ID
Mode of Action, Properties, Production, and Application of Laccase: A Review.Recent Pat Biotechnol2018 Aug 2130147019
Zerovalent iron and iron(VI): Effective means for the removal of psychoactivepharmaceuticals and illicit drugs from wastewaters.Sci Total Environ2016 Jan 126376114
Presence of pharmaceuticals and heavy metals in the waters of a Mediterraneancoastal wetland: Potential interactions and the influence of the environment.Sci Total Environ2016 Jan 126354171
Breast Milk and Hair Testing to Detect Illegal Drugs, Nicotine, and Caffeine in Donors to a Human Milk Bank.J Hum Lact2016 Aug27197576
One step green synthesis of silver nano/microparticles using extracts ofTrachyspermum ammi and Papaver somniferum.Colloids Surf B Biointerfaces2012 Jun 122348989
Pharmacokinetics, intraoperative effect and postoperative analgesia of tramadolin cats.Res Vet Sci2011 Jun20708759
Suppressive effect of pectic polysaccharides from Cucurbita pepo L. var. Styriacaon citric acid-induced cough reflex in guinea pigs.Fitoterapia2011 Apr21062638
Sickle cell disease.BMJ Clin Evid2009 Mar 2719445751
Risk to the breast-fed neonate from codeine treatment to the mother: a quantitative mechanistic modeling study.Clin Pharmacol Ther2009 Dec19710640
Safety of codeine during breastfeeding: fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine.Can Fam Physician2007 Jan17872605
[Novel potential uses of thalidomide in the management of pain? A review of theliterature].Schmerz2003 Jun12789488
An evaluation of protein assays for quantitative determination of drugs.J Biochem Biophys Methods2003 Jul 3112834962
Use of antibiotic and analgesic drugs during lactation.Drug Saf200314583068
[Determination of Pericarpium papaveris in foods accompanied with some fragrantsubstances by high performance liquid chromatography].Se Pu2000 Nov12541749
[Determination of pericarpium papaveris(yingsuqiao) in bottom material of chafingdish by high performance liquid chromatography(HPLC)].Se Pu1999 Jul12552865
Effect of subacute toxic levels of dietary cyclopropenoid fatty acids upon membrane function and fatty acid composition in the rat.Lipids1974 May4833195

Targets

General Function:
Voltage-gated calcium channel activity
Specific Function:
Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors. The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extend to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B. Also couples to adenylate cyclase stimulatory G alpha proteins. The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization. Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction. The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins. The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation. Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling. Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling. Endogenous ligands induce rapid desensitization, endocytosis and recycling whereas morphine induces only low desensitization and endocytosis. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties. Involved in neurogenesis. Isoform 12 couples to GNAS and is proposed to be involved in excitatory effects. Isoform 16 and isoform 17 do not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity.
Gene Name:
OPRM1
Uniprot ID:
P35372
Molecular Weight:
44778.855 Da
Mechanism of Action:
Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Codeine's analgesic activity is, most likely, due to its conversion to morphine. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
References
  1. Venhorst J, ter Laak AM, Commandeur JN, Funae Y, Hiroi T, Vermeulen NP: Homology modeling of rat and human cytochrome P450 2D (CYP2D) isoforms and computational rationalization of experimental ligand-binding specificities. J Med Chem. 2003 Jan 2;46(1):74-86. [12502361 ]
General Function:
Opioid receptor activity
Specific Function:
G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain and in opiate-mediated analgesia. Plays a role in developing analgesic tolerance to morphine.
Gene Name:
OPRD1
Uniprot ID:
P41143
Molecular Weight:
40368.235 Da
Mechanism of Action:
Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Codeine's analgesic activity is, most likely, due to its conversion to morphine. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.
References
  1. Ortiz MI, Castro-Olguin J, Pena-Samaniego N, Castaneda-Hernandez G: Probable activation of the opioid receptor-nitric oxide-cyclic GMP-K+ channels pathway by codeine. Pharmacol Biochem Behav. 2005 Dec;82(4):695-703. Epub 2006 Jan 4. [16386786 ]
General Function:
Opioid receptor activity
Specific Function:
G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synthetic opioids and for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain. Plays a role in mediating reduced physical activity upon treatment with synthetic opioids. Plays a role in the regulation of salivation in response to synthetic opioids. May play a role in arousal and regulation of autonomic and neuroendocrine functions.
Gene Name:
OPRK1
Uniprot ID:
P41145
Molecular Weight:
42644.665 Da
Mechanism of Action:
Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Codeine's analgesic activity is, most likely, due to its conversion to morphine. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
General Function:
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function:
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr). Isoforms USO have no channel activity by themself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation.
Gene Name:
KCNH2
Uniprot ID:
Q12809
Molecular Weight:
126653.52 Da
References
  1. Tobita M, Nishikawa T, Nagashima R: A discriminant model constructed by the support vector machine method for HERG potassium channel inhibitors. Bioorg Med Chem Lett. 2005 Jun 2;15(11):2886-90. [15911273 ]