T3DB: Propoxyphene

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (3)XML

Targets (3)

Record Information

Version

2.0

Creation Date

2009-07-21 20:27:20 UTC

Update Date

2014-12-24 20:25:52 UTC

Accession Number

T3D2848

Identification

Common Name

Propoxyphene

Class

Small Molecule

Description

Propoxyphene 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

MOL SDF 3D-SDF PDB SMILES InChI View 3D Structure

Synonyms

Synonym
Abalgin
D-Propoxyphene
Dacoton
Darvon
Darvon-N
Deprancol
Depronal
Destropropossifene
Dextropropoxifeno
Dextropropoxyphen
Dextropropoxyphene
Dextropropoxyphene-M
Dextropropoxyphenum
Dextroproxifeno
Dolene
Doloxene

Chemical Formula

C₂₂H₂₉NO₂

Average Molecular Mass

339.471 g/mol

Monoisotopic Mass

339.220 g/mol

CAS Registry Number

469-62-5

IUPAC Name

(2S,3R)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl propanoate

Traditional Name

propoxyphene

SMILES

[H][C@](C)(CN(C)C)[C@@](CC1=CC=CC=C1)(OC(=O)CC)C1=CC=CC=C1

InChI Identifier

InChI=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 Key

InChIKey=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.

Kingdom

Organic compounds

Super Class

Phenylpropanoids and polyketides

Class

Stilbenes

Sub Class

Not Available

Direct Parent

Stilbenes

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 Framework

Aromatic homomonocyclic compounds

External Descriptors

1-benzyl-3-(dimethylamino)-2-methyl-1-phenylpropyl propanoate (CHEBI:51173 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Biological Roles

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	75.5°C
Boiling Point	Not Available
Solubility	3.32 mg/L (at 25°C)
LogP	4.18

Predicted Properties

Property	Value	Source
Water Solubility	0.0042 g/L	ALOGPS
logP	4.06	ALOGPS
logP	4.9	ChemAxon
logS	-4.9	ALOGPS
pKa (Strongest Basic)	9.52	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	2	ChemAxon
Hydrogen Donor Count	0	ChemAxon
Polar Surface Area	29.54 Å²	ChemAxon
Rotatable Bond Count	9	ChemAxon
Refractivity	102.88 m³·mol⁻¹	ChemAxon
Polarizability	38.86 Å³	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
GC-MS	GC-MS Spectrum - CI-B (Non-derivatized)	splash10-067l-0393000000-d81188159d7476252fd4	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - EI-B (Non-derivatized)	splash10-0a4i-9000000000-9c987f1baf068ed1fd6e	2017-09-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0a4i-9310000000-64090a7cc1eb41e95d27	2017-08-28	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-052f-5097000000-14ee532e398ad87fafa7	2017-07-26	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0aor-7391000000-99df9afa035ec5903954	2017-07-26	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0a4l-9650000000-250ef3abb6af95e8d3b3	2017-07-26	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-000i-3059000000-8b5a0ccf0362c5cb5fab	2017-07-26	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0540-5194000000-be7207ca388dafc238ca	2017-07-26	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0pb9-9270000000-ca80d8ae975fd75212c7	2017-07-26	View Spectrum
MS	Mass Spectrum (Electron Ionization)	splash10-0a4i-9200000000-39d80ee06dde3e5036f4	2014-09-20	View Spectrum

Toxicity Profile

Route of Exposure

Oral

Mechanism of Toxicity

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.

Metabolism

Hepatic 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 Values

LD50: 230mg/kg (oral, rat)

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

For the relief of mild to moderate pain

Minimum Risk Level

Not Available

Health Effects

Medical problems can include congested lungs, liver disease, tetanus, infection of the heart valves, skin abscesses, anemia and pneumonia. Death can occur from overdose.

Symptoms

Coma, respiratory depression, circulatory collapse, and pulmonary edema. Seizures occur more frequently in patients with propoxyphene intoxication than in those with opiate intoxication.

Treatment

Attention 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

External Links

DrugBank ID

DB00647

HMDB ID

HMDB14785

PubChem Compound ID

25137868

ChEMBL ID

Not Available

ChemSpider ID

21864756

KEGG ID

C07406

UniProt ID

Not Available

OMIM ID

ChEBI ID

51173

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Propoxyphene

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Propoxyphene

References

Synthesis Reference

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

MSDS

Link

General References

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 ]
Drugs.com [Link]
RxList: The Internet Drug Index (2009). [Link]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. Delta-type opioid receptor

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

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 ]
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 ]
Wu C, Fry CH, Henry JA: Membrane toxicity of opioids measured by protozoan motility. Toxicology. 1997 Feb 14;117(1):35-44. [9020197 ]
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 ]
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 ]

Target Details

2. Mu-type opioid receptor

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

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
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 ]
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 ]
Tyers MB: A classification of opiate receptors that mediate antinociception in animals. Br J Pharmacol. 1980 Jul;69(3):503-12. [6249436 ]
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 ]

Target Details

3. Kappa-type opioid receptor

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

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]

Propoxyphene (T3D2848)

Structure for T3D2848: Propoxyphene

Targets

References

References

References