You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on Toxin, Toxin Target Database.
Record Information
Version2.0
Creation Date2009-07-21 20:27:20 UTC
Update Date2014-12-24 20:25:52 UTC
Accession NumberT3D2848
Identification
Common NamePropoxyphene
ClassSmall Molecule
DescriptionPropoxyphene is only found in individuals that have used or taken this drug. It is a narcotic analgesic structurally related to methadone. Only the dextro-isomer has an analgesic effect; the levo-isomer appears to exert an antitussive effect. [PubChem]Propoxyphene acts as a weak agonist at OP1, OP2, and OP3 opiate receptors within the central nervous system (CNS). Propoxyphene primarily affects OP3 receptors, which are coupled with G-protein receptors and function as modulators, both positive and negative, 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 such as propoxyphene also inhibit the release of vasopressin, somatostatin, insulin, and glucagon. 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.
Compound Type
  • Amine
  • Analgesic
  • Analgesic, Opioid
  • Antitussive Agent
  • Drug
  • Ester
  • Ether
  • Metabolite
  • Narcotic
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
Abalgin
D-Propoxyphene
Dacoton
Darvon
Darvon-N
Deprancol
Depronal
Destropropossifene
Dextropropoxifeno
Dextropropoxyphen
Dextropropoxyphene
Dextropropoxyphene-M
Dextropropoxyphenum
Dextroproxifeno
Dolene
Doloxene
Chemical FormulaC22H29NO2
Average Molecular Mass339.471 g/mol
Monoisotopic Mass339.220 g/mol
CAS Registry Number469-62-5
IUPAC Name(2S,3R)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl propanoate
Traditional Namepropoxyphene
SMILES[H][C@](C)(CN(C)C)[C@@](CC1=CC=CC=C1)(OC(=O)CC)C1=CC=CC=C1
InChI IdentifierInChI=1/C22H29NO2/c1-5-21(24)25-22(18(2)17-23(3)4,20-14-10-7-11-15-20)16-19-12-8-6-9-13-19/h6-15,18H,5,16-17H2,1-4H3/t18-,22+/s2
InChI KeyInChIKey=XLMALTXPSGQGBX-PEODTPIXNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassStilbenes
Sub ClassNot Available
Direct ParentStilbenes
Alternative Parents
Substituents
  • Stilbene
  • Phenylbutylamine
  • Benzyloxycarbonyl
  • Phenylpropane
  • Aralkylamine
  • Monocyclic benzene moiety
  • Benzenoid
  • Tertiary aliphatic amine
  • Tertiary amine
  • Carboxylic acid ester
  • Amino acid or derivatives
  • Monocarboxylic acid or derivatives
  • Carboxylic acid derivative
  • Organic oxide
  • Organopnictogen compound
  • Organic oxygen compound
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Organic nitrogen compound
  • Amine
  • Hydrocarbon derivative
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
  • 1-benzyl-3-(dimethylamino)-2-methyl-1-phenylpropyl propanoate (CHEBI:51173 )
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 Point75.5°C
Boiling PointNot Available
Solubility3.32 mg/L (at 25°C)
LogP4.18
Predicted Properties
PropertyValueSource
Water Solubility0.0042 g/LALOGPS
logP4.06ALOGPS
logP4.9ChemAxon
logS-4.9ALOGPS
pKa (Strongest Basic)9.52ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area29.54 ŲChemAxon
Rotatable Bond Count9ChemAxon
Refractivity102.88 m³·mol⁻¹ChemAxon
Polarizability38.86 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)splash10-067l-0393000000-d81188159d7476252fd4JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0a4i-9000000000-9c987f1baf068ed1fd6eJSpectraViewer | MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0a4i-9310000000-64090a7cc1eb41e95d27JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-052f-5097000000-14ee532e398ad87fafa7JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0aor-7391000000-99df9afa035ec5903954JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0a4l-9650000000-250ef3abb6af95e8d3b3JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-000i-3059000000-8b5a0ccf0362c5cb5fabJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0540-5194000000-be7207ca388dafc238caJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0pb9-9270000000-ca80d8ae975fd75212c7JSpectraViewer
MSMass Spectrum (Electron Ionization)splash10-0a4i-9200000000-39d80ee06dde3e5036f4JSpectraViewer | MoNA
Toxicity Profile
Route of ExposureOral
Mechanism of ToxicityPropoxyphene acts as a weak agonist at OP1, OP2, and OP3 opiate receptors within the central nervous system (CNS). Propoxyphene primarily affects OP3 receptors, which are coupled with G-protein receptors and function as modulators, both positive and negative, 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 such as propoxyphene also inhibit the release of vasopressin, somatostatin, insulin, and glucagon. 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.
MetabolismHepatic Route of Elimination: The major route of metabolism is cytochrome CYP3A4 mediated N-demethylation to norpropoxyphene, which is excreted by the kidneys. In 48 hours, approximately 20% to 25% of the administered dose of propoxyphene is excreted via the urine, most of which is free or conjugated norpropoxyphene. Half Life: 6-12 hours
Toxicity ValuesLD50: 230mg/kg (oral, rat)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the relief of mild to moderate pain
Minimum Risk LevelNot Available
Health EffectsMedical problems can include congested lungs, liver disease, tetanus, infection of the heart valves, skin abscesses, anemia and pneumonia. Death can occur from overdose.
SymptomsComa, respiratory depression, circulatory collapse, and pulmonary edema. Seizures occur more frequently in patients with propoxyphene intoxication than in those with opiate intoxication.
TreatmentAttention should be directed first to establishing a patent airway and to restoring ventilation. Mechanically assisted ventilation, with or without oxygen, may be required, and positive pressure respiration may be desirable if pulmonary edema is present. The narcotic antagonist naloxone will markedly reduce the degree of respiratory depression, and 0.4 to 2 mg should be administered promptly, preferably intravenously. If the desired degree of counteraction with improvement in respiratory functions is not obtained, naloxone should be repeated at 2- to 3-minute intervals. The duration of action of the antagonist may be brief. If no response is observed after 10 mg of naloxone have been administered, the diagnosis of propoxyphene toxicity should be questioned. Naloxone may also be administered by continuous intravenous infusion. (3)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00647
HMDB IDHMDB14785
PubChem Compound ID25137868
ChEMBL IDNot Available
ChemSpider ID21864756
KEGG IDC07406
UniProt IDNot Available
OMIM ID
ChEBI ID51173
BioCyc IDNot Available
CTD IDNot Available
Stitch IDPropoxyphene
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkPropoxyphene
References
Synthesis Reference

Carl R. White, “Synthesis and purification of d-propoxyphene hydrochloride.” U.S. Patent US4661625, issued April, 1973.

MSDSLink
General References
  1. Coda BA, Rudy AC, Archer SM, Wermeling DP: Pharmacokinetics and bioavailability of single-dose intranasal hydromorphone hydrochloride in healthy volunteers. Anesth Analg. 2003 Jul;97(1):117-23, table of contents. [12818953 ]
  2. Drugs.com [Link]
  3. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

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
References
  1. Neil A, Terenius L: d-Propoxyphene acts differently from morphine on opioid receptor-effector mechanisms. Eur J Pharmacol. 1981 Jan 5;69(1):33-9. [6258941 ]
  2. Grandvuillemin A, Jolimoy G, Authier F, Dautriche A, Duhoux F, Sgro C: [Tramadol-induced hypoglycemia. 2 cases]. Presse Med. 2006 Dec;35(12 Pt 1):1842-4. [17159739 ]
  3. Wu C, Fry CH, Henry JA: Membrane toxicity of opioids measured by protozoan motility. Toxicology. 1997 Feb 14;117(1):35-44. [9020197 ]
  4. Ebert B, Thorkildsen C, Andersen S, Christrup LL, Hjeds H: Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists. Biochem Pharmacol. 1998 Sep 1;56(5):553-9. [9783723 ]
  5. Hayes AG, Skingle M, Tyers MB: Evaluation of the receptor selectivities of opioid drugs by investigating the block of their effect on urine output by beta-funaltrexamine. J Pharmacol Exp Ther. 1987 Mar;240(3):984-8. [3559988 ]
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
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Picker MJ: Discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine: cross-substitution by mu and delta opioid agonists. J Pharmacol Exp Ther. 1997 Dec;283(3):1009-17. [9399970 ]
  3. Ulens C, Daenens P, Tytgat J: Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents. Cardiovasc Res. 1999 Dec;44(3):568-78. [10690289 ]
  4. Tyers MB: A classification of opiate receptors that mediate antinociception in animals. Br J Pharmacol. 1980 Jul;69(3):503-12. [6249436 ]
  5. Codd EE, Shank RP, Schupsky JJ, Raffa RB: Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther. 1995 Sep;274(3):1263-70. [7562497 ]
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
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]