Codeine
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Basic Info
Common Name | Codeine(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 ID | F04746 |
CAS Number | 76-57-3 |
PubChem CID | 5284371 |
Formula | C18H21NO3 |
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 |
Wikipedia | Codeine |
Synonyms | codeine Methylmorphine Codeine anhydrous Codicept l-Codeine Coducept Morphine monomethyl ether Morphine 3-methyl ether (-)-Codeine 76-57-3 |
Classifies | Predicted: Pollutant |
Update Date | Nov 13, 2018 17:07 |
Chemical Taxonomy
Kingdom | Organic compounds |
Superclass | Alkaloids and derivatives |
Class | Morphinans |
Subclass | Not available |
Intermediate Tree Nodes | Not available |
Direct Parent | Morphinans |
Alternative Parents | |
Molecular Framework | Aromatic heteropolycyclic compounds |
Substituents | Morphinan - 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 |
Description | This 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 Name | Property Value |
---|---|
Molecular Weight | 299.37 |
Hydrogen Bond Donor Count | 1 |
Hydrogen Bond Acceptor Count | 4 |
Rotatable Bond Count | 1 |
Complexity | 509 |
Monoisotopic Mass | 299.152 |
Exact Mass | 299.152 |
XLogP | 1.1 |
Formal Charge | 0 |
Heavy Atom Count | 22 |
Defined Atom Stereocenter Count | 5 |
Undefined Atom Stereocenter Count | 0 |
Defined Bond Stereocenter Count | 0 |
Undefined Bond Stereocenter Count | 0 |
Isotope Atom Count | 0 |
Covalently-Bonded Unit Count | 1 |
ADMET
Model | Result | Probability |
---|---|---|
Absorption | ||
Blood-Brain Barrier | BBB+ | 0.9979 |
Human Intestinal Absorption | HIA+ | 0.9966 |
Caco-2 Permeability | Caco2+ | 0.8867 |
P-glycoprotein Substrate | Substrate | 0.8631 |
P-glycoprotein Inhibitor | Inhibitor | 0.5435 |
Non-inhibitor | 0.8724 | |
Renal Organic Cation Transporter | Inhibitor | 0.6380 |
Distribution | ||
Subcellular localization | Mitochondria | 0.4895 |
Metabolism | ||
CYP450 2C9 Substrate | Non-substrate | 0.7698 |
CYP450 2D6 Substrate | Substrate | 0.9274 |
CYP450 3A4 Substrate | Substrate | 0.7796 |
CYP450 1A2 Inhibitor | Non-inhibitor | 0.6494 |
CYP450 2C9 Inhibitor | Non-inhibitor | 0.8866 |
CYP450 2D6 Inhibitor | Inhibitor | 0.6978 |
CYP450 2C19 Inhibitor | Non-inhibitor | 0.8256 |
CYP450 3A4 Inhibitor | Non-inhibitor | 0.8899 |
CYP Inhibitory Promiscuity | Low CYP Inhibitory Promiscuity | 0.7470 |
Excretion | ||
Toxicity | ||
Human Ether-a-go-go-Related Gene Inhibition | Weak inhibitor | 0.8556 |
Non-inhibitor | 0.8615 | |
AMES Toxicity | Non AMES toxic | 0.9133 |
Carcinogens | Non-carcinogens | 0.9567 |
Fish Toxicity | High FHMT | 0.8941 |
Tetrahymena Pyriformis Toxicity | High TPT | 0.8916 |
Honey Bee Toxicity | Low HBT | 0.5107 |
Biodegradation | Not ready biodegradable | 0.9935 |
Acute Oral Toxicity | II | 0.7450 |
Carcinogenicity (Three-class) | Non-required | 0.7141 |
Model | Value | Unit |
---|---|---|
Absorption | ||
Aqueous solubility | -2.0336 | LogS |
Caco-2 Permeability | 1.5243 | LogPapp, cm/s |
Distribution | ||
Metabolism | ||
Excretion | ||
Toxicity | ||
Rat Acute Toxicity | 2.8450 | LD50, mol/kg |
Fish Toxicity | 0.7325 | pLC50, mg/L |
Tetrahymena Pyriformis Toxicity | 0.8107 | pIGC50, ug/L |
References
Title | Journal | Date | Pubmed ID |
---|---|---|---|
Mode of Action, Properties, Production, and Application of Laccase: A Review. | Recent Pat Biotechnol | 2018 Aug 21 | 30147019 |
Zerovalent iron and iron(VI): Effective means for the removal of psychoactivepharmaceuticals and illicit drugs from wastewaters. | Sci Total Environ | 2016 Jan 1 | 26376114 |
Presence of pharmaceuticals and heavy metals in the waters of a Mediterraneancoastal wetland: Potential interactions and the influence of the environment. | Sci Total Environ | 2016 Jan 1 | 26354171 |
Breast Milk and Hair Testing to Detect Illegal Drugs, Nicotine, and Caffeine in Donors to a Human Milk Bank. | J Hum Lact | 2016 Aug | 27197576 |
One step green synthesis of silver nano/microparticles using extracts ofTrachyspermum ammi and Papaver somniferum. | Colloids Surf B Biointerfaces | 2012 Jun 1 | 22348989 |
Pharmacokinetics, intraoperative effect and postoperative analgesia of tramadolin cats. | Res Vet Sci | 2011 Jun | 20708759 |
Suppressive effect of pectic polysaccharides from Cucurbita pepo L. var. Styriacaon citric acid-induced cough reflex in guinea pigs. | Fitoterapia | 2011 Apr | 21062638 |
Sickle cell disease. | BMJ Clin Evid | 2009 Mar 27 | 19445751 |
Risk to the breast-fed neonate from codeine treatment to the mother: a quantitative mechanistic modeling study. | Clin Pharmacol Ther | 2009 Dec | 19710640 |
Safety of codeine during breastfeeding: fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. | Can Fam Physician | 2007 Jan | 17872605 |
[Novel potential uses of thalidomide in the management of pain? A review of theliterature]. | Schmerz | 2003 Jun | 12789488 |
An evaluation of protein assays for quantitative determination of drugs. | J Biochem Biophys Methods | 2003 Jul 31 | 12834962 |
Use of antibiotic and analgesic drugs during lactation. | Drug Saf | 2003 | 14583068 |
[Determination of Pericarpium papaveris in foods accompanied with some fragrantsubstances by high performance liquid chromatography]. | Se Pu | 2000 Nov | 12541749 |
[Determination of pericarpium papaveris(yingsuqiao) in bottom material of chafingdish by high performance liquid chromatography(HPLC)]. | Se Pu | 1999 Jul | 12552865 |
Effect of subacute toxic levels of dietary cyclopropenoid fatty acids upon membrane function and fatty acid composition in the rat. | Lipids | 1974 May | 4833195 |
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
- 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
- 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
- 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
- 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
- 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 ]