Dextropropoxyphene

Overview

Description
A painkiller used to treat mild to moderate pain.
Description
A painkiller used to treat mild to moderate pain.
DrugBank ID
DB00647
Type
Small Molecule
US Approved
YES
Other Approved
YES
Clinical Trials
Phase 0
0
Phase 1
0
Phase 2
0
Phase 3
0
Phase 4
8
Therapeutic Categories
  • Opioid Agonist

Identification

Summary

Dextropropoxyphene is an opioid analgesic used to treat mild to moderate pain.

Brand Names
Darvocet-N, Darvon
Generic Name
Dextropropoxyphene
DrugBank Accession Number
DB00647
Background

Dextropropoxyphene is an opioid analgesic manufactured by Eli Lilly and Company. It is used in the symptomatic treatment of mild pain. It displays antitussive and local anaesthetic actions. Due to the risk of cardiac arrhythmias and overdose, possibly leading to death, dextropropoxyphene has been withdrawn from the market in Europe and the United States. The drug is often referred to as the general form, "propoxyphene", however only the dextro-isomer (dextropropoxyphene) has any analgesic effect. The levo-isomer appears to exhibit a very limited antitussive effect.

Type
Small Molecule
Groups
Approved, Illicit, Investigational, Withdrawn
Structure
Weight
Average: 339.4712
Monoisotopic: 339.219829177
Chemical Formula
C22H29NO2
Synonyms
  • d-Propoxyphene
  • Destropropossifene
  • Dextropropoxifeno
  • Dextropropoxyphen
  • Dextropropoxyphène
  • Dextropropoxyphene
  • Dextropropoxyphenum
  • Dextroproxifeno
  • Propoxyphene
External IDs
  • IDS-ND-004(SECT.2)
  • J5.928E
  • L 16298
  • SK 65
  • SK-65

Pharmacology

Indication

For the relief of mild to moderate pain.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofPain••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Propoxyphene, a synthetic opiate agonist, is structurally similar to methadone. Its general pharmacologic properties are those of the opiates as a group. The analgesic effect of propoxyphene is due to the d-isomer, dextropropoxyphene. It binds to the opiate receptors and leads to a decrease of the perception of pain stimuli. Propoxyphene possesses little to no antitussive activity and no antipyretic action.

Mechanism of action

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.

TargetActionsOrganism
AMu-type opioid receptor
agonist
Humans
ADelta-type opioid receptor
agonist
Humans
AKappa-type opioid receptor
antagonist
Humans
ULiver carboxylesterase 1Not AvailableHumans
UNMDA receptor
antagonist
Humans
Absorption

Not Available

Volume of distribution
  • 16 L/kg
Protein binding

Not Available

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

Clearance
  • 2.6 L/min
Adverse Effects
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Toxicity

Coma, respiratory depression, circulatory collapse, and pulmonary edema. Seizures occur more frequently in patients with propoxyphene intoxication than in those with opiate intoxication. LD50=230mg/kg (orally in rat, Emerson)

Pathways
PathwayCategory
Propoxyphene Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
1,2-BenzodiazepineThe risk or severity of adverse effects can be increased when Dextropropoxyphene is combined with 1,2-Benzodiazepine.
AbametapirThe serum concentration of Dextropropoxyphene can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Dextropropoxyphene can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Dextropropoxyphene.
AbirateroneThe metabolism of Dextropropoxyphene can be decreased when combined with Abiraterone.
Food Interactions
  • Avoid alcohol.
  • Take with or without food. Food does not significantly affect absorption.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Dextropropoxyphene hydrochlorideCB2TL9PS0T1639-60-7QMQBBUPJKANITL-MYXGOWFTSA-N
Dextropropoxyphene napsylate38M219L1OJ26570-10-5GBKONKCASNNUQD-VGHSCWAPSA-N
Product Images
International/Other Brands
Abalgin (DLF) / Dacoton (Standard) / Deprancol (Parke Davis) / Depronal (Pfizer) / Dolene / Doloxene (Aspen Pharmacare)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
642 TabTablet65 mgOralPendopharm Division Of Pharmascience Inc1968-12-312010-11-25Canada flag
DarvonCapsule65 mg/1OralXanodyne Pharmaceuticals2009-09-252010-11-19US flag
Darvon-NCapsule100 mgOralPaladin Labs Inc.1973-12-312010-12-23Canada flag
Darvon-NTablet, film coated100 mg/1OralXanodyne Pharmaceuticals2009-09-252010-11-19US flag
Darvon-NTablet, film coated100 mg/1OralPhysicians Total Care, Inc.2007-01-082008-06-30US flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Novo-propoxyn Cap 65mgCapsule65 mgOralNovopharm Limited1970-12-312005-08-10Canada flag
PropoxypheneCapsule65 mg/1OralWest-Ward Pharmaceuticals Corp.1973-06-202010-11-24US flag
PropoxypheneCapsule65 mg/1OralPD-Rx Pharmaceuticals, Inc.2010-05-102015-05-08US flag
PropoxypheneCapsule65 mg/1OralStat Rx USA2009-10-27Not applicableUS flag
PropoxypheneCapsule65 mg/1OralPD-Rx Pharmaceuticals, Inc.1973-06-202015-05-08US flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
692 TabDextropropoxyphene hydrochloride (65 mg) + Acetylsalicylic acid (375 mg) + Caffeine (30 mg)TabletOralMerck Frosst Canada & Cie, Merck Frosst Canada & Co.1986-02-131998-04-21Canada flag
692 TabletDextropropoxyphene hydrochloride (65 mg) + Acetylsalicylic acid (375 mg) + Caffeine (30 mg)TabletOralLioh Inc.1998-09-012006-08-25Canada flag
Balacet 325Dextropropoxyphene napsylate (100 mg/1) + Acetaminophen (325 mg/1)Tablet, film coatedOralCornerstone Therapeutics Inc.2004-06-282010-08-10US flag
Balacet 325Dextropropoxyphene napsylate (100 mg/1) + Acetaminophen (325 mg/1)Tablet, film coatedOralCornerstone Therapeutics Inc.2004-06-282010-11-19US flag
Darvocet A500Dextropropoxyphene napsylate (100 mg/1) + Acetaminophen (500 mg/1)Tablet, film coatedOralXanodyne Pharmaceuticals2009-11-302010-11-19US flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Therapoxyphene 650Dextropropoxyphene napsylate (100 mg/1) + Acetaminophen (650 mg/1)TabletOralPhysician Therapeutics Llc2010-10-142010-12-03US flag

Categories

ATC Codes
N02AC04 — DextropropoxypheneN02AC54 — Dextropropoxyphene, combinations excl. psycholepticsN02AC74 — Dextropropoxyphene, combinations with psycholeptics
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound 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
Phenylbutylamines / Benzyloxycarbonyls / Phenylpropanes / Aralkylamines / Trialkylamines / Carboxylic acid esters / Amino acids and derivatives / Monocarboxylic acids and derivatives / Organopnictogen compounds / Organic oxides
show 2 more
Substituents
Amine / Amino acid or derivatives / Aralkylamine / Aromatic homomonocyclic compound / Benzenoid / Benzyloxycarbonyl / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Hydrocarbon derivative
show 13 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
1-benzyl-3-(dimethylamino)-2-methyl-1-phenylpropyl propanoate (CHEBI:51173)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
S2F83W92TK
CAS number
469-62-5
InChI Key
XLMALTXPSGQGBX-GCJKJVERSA-N
InChI
InChI=1S/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+/m1/s1
IUPAC Name
(2S,3R)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl propanoate
SMILES
CCC(=O)O[C@@](CC1=CC=CC=C1)([C@H](C)CN(C)C)C1=CC=CC=C1

References

Synthesis Reference

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

US4661625
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. [Article]
  2. 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. [Article]
  3. Tyers MB: A classification of opiate receptors that mediate antinociception in animals. Br J Pharmacol. 1980 Jul;69(3):503-12. [Article]
  4. FDA data [Link]
  5. Drug Information [Link]
  6. Drugs.com [Link]
KEGG Drug
D07809
KEGG Compound
C07406
PubChem Compound
10100
PubChem Substance
46506690
ChemSpider
9696
BindingDB
82269
RxNav
8785
ChEBI
51173
ChEMBL
CHEMBL1213351
ZINC
ZINC000001530769
Therapeutic Targets Database
DAP000017
PharmGKB
PA451142
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Dextropropoxyphene
MSDS
Download (46.1 KB)

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
4CompletedSupportive CarePain / Unspecified Adult Solid Tumor, Protocol Specific1somestatusstop reasonjust information to hide
4TerminatedTreatmentHealthy Volunteers (HV)1somestatusstop reasonjust information to hide
4TerminatedTreatmentSpinal Stenosis of Lumbar Region1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
  • Xanodyne pharmaceutics inc
  • Heritage pharmaceuticals inc
  • Mk laboratories inc
  • Halsey drug co inc
  • Alra laboratories inc
  • Impax laboratories inc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mutual pharmaceutical co inc
  • Mylan pharmaceuticals inc
  • Nexgen pharma inc
  • Par pharmaceutical inc
  • Purepac pharmaceutical co
  • Private formulations inc
  • Roxane laboratories inc
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Valeant pharmaceuticals international
  • Vintage pharmaceuticals inc
  • Watson laboratories inc
  • West ward pharmaceutical corp
  • Whiteworth towne paulsen inc
  • Warner chilcott div warner lambert co
  • Aaipharma llc
Packagers
  • AAIPharma Inc.
  • Aidarex Pharmacuticals LLC
  • Altura Pharmaceuticals Inc.
  • Amerisource Health Services Corp.
  • Apotheca Inc.
  • Aristos Pharmaceuticals
  • A-S Medication Solutions LLC
  • Blenheim Pharmacal
  • Bryant Ranch Prepack
  • Cardinal Health
  • Caremark LLC
  • Comprehensive Consultant Services Inc.
  • Corepharma LLC
  • Cornerstone Pharmacy
  • D.M. Graham Laboratories Inc.
  • Direct Dispensing Inc.
  • Dispensing Solutions
  • Diversified Healthcare Services Inc.
  • DSM Corp.
  • Golden State Medical Supply Inc.
  • H and H Laboratories
  • H.J. Harkins Co. Inc.
  • Heartland Repack Services LLC
  • Innoviant Pharmacy Inc.
  • Ivax Pharmaceuticals
  • Kaiser Foundation Hospital
  • Keltman Pharmaceuticals Inc.
  • Lake Erie Medical and Surgical Supply
  • Liberty Pharmaceuticals
  • Lilly Del Caribe Inc.
  • Major Pharmaceuticals
  • Mallinckrodt Inc.
  • Mckesson Corp.
  • Medvantx Inc.
  • Mikart Inc.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Nexgen Pharma Inc.
  • Nucare Pharmaceuticals Inc.
  • Palmetto Pharmaceuticals Inc.
  • Par Pharmaceuticals
  • PCA LLC
  • PD-Rx Pharmaceuticals Inc.
  • Pharmedix
  • Physicians Total Care Inc.
  • Pliva Inc.
  • Preferred Pharmaceuticals Inc.
  • Prepackage Specialists
  • Prepak Systems Inc.
  • Qualitest
  • Ranbaxy Laboratories
  • Rebel Distributors Corp.
  • Redpharm Drug
  • Remedy Repack
  • Resource Optimization and Innovation LLC
  • Sandhills Packaging Inc.
  • Smartscience Laboratories Inc.
  • Southwood Pharmaceuticals
  • St Mary's Medical Park Pharmacy
  • Stat Rx Usa
  • Talbert Medical Management Corp.
  • Teva Pharmaceutical Industries Ltd.
  • UDL Laboratories
  • Va Cmop Dallas
  • Veratex Corp.
  • Vintage Pharmaceuticals Inc.
  • Watson Pharmaceuticals
  • West-Ward Pharmaceuticals
  • Wockhardt Ltd.
  • Xanodyne Pharmaceuticals Inc.
Dosage Forms
FormRouteStrength
TabletOral65 mg
CapsuleOral
CapsuleOral100 mg
Tablet, film coatedOral100 mg/1
Pill
Suppository
CapsuleOral65 mg
CapsuleOral65 mg/1
TabletOral
Tablet, film coatedOral
Prices
Unit descriptionCostUnit
Propoxyphene napsylate powder5.33USD g
Darvon-n 100 mg tablet2.16USD tablet
Darvon 65 mg capsule1.71USD capsule
Propoxyphene N-APAP 100-500 mg tablet1.6USD tablet
Darvon 65 mg pulvule1.49USD each
Propoxyphene N-APAP 50-325 mg tablet1.32USD tablet
Propoxyphene-APAP 65-650 mg tablet0.57USD tablet
Propoxyphene N-APAP 100-650 mg tablet0.47USD tablet
Propoxyphene hcl 65 mg capsule0.43USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)75.5 °CPhysProp
water solubility3.32 mg/L (at 25 °C)MCFARLAND,JW ET AL. (2001)
logP4.18HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.00419 mg/mLALOGPS
logP4.06ALOGPS
logP4.9Chemaxon
logS-4.9ALOGPS
pKa (Strongest Basic)9.52Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count2Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area29.54 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity102.88 m3·mol-1Chemaxon
Polarizability38.86 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleYesChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.997
Blood Brain Barrier+0.9503
Caco-2 permeable+0.7277
P-glycoprotein substrateSubstrate0.5798
P-glycoprotein inhibitor IInhibitor0.7851
P-glycoprotein inhibitor IINon-inhibitor0.6469
Renal organic cation transporterNon-inhibitor0.6086
CYP450 2C9 substrateNon-substrate0.833
CYP450 2D6 substrateNon-substrate0.9117
CYP450 3A4 substrateSubstrate0.6032
CYP450 1A2 substrateInhibitor0.6357
CYP450 2C9 inhibitorNon-inhibitor0.7637
CYP450 2D6 inhibitorInhibitor0.6887
CYP450 2C19 inhibitorNon-inhibitor0.7628
CYP450 3A4 inhibitorNon-inhibitor0.7992
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.646
Ames testNon AMES toxic0.8896
CarcinogenicityCarcinogens 0.7164
BiodegradationNot ready biodegradable0.9714
Rat acute toxicity2.9360 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9033
hERG inhibition (predictor II)Inhibitor0.6837
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0a4i-9310000000-64090a7cc1eb41e95d27
GC-MS Spectrum - CI-BGC-MSsplash10-067l-0393000000-d81188159d7476252fd4
GC-MS Spectrum - EI-BGC-MSsplash10-0a4i-9000000000-9c987f1baf068ed1fd6e
Mass Spectrum (Electron Ionization)MSsplash10-0a4i-9200000000-39d80ee06dde3e5036f4
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-3190000000-23a4e1c3e4e618c63c87
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-00di-9120000000-f76f3d90103e0de058a4
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-006x-4980000000-2aa2d32e113bce505fb7
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-9150000000-07d3369247f880b91798
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0ufv-0690000000-6be347209ba89b1056b0
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-9140000000-cdacdd2543f8eb2c60b9
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-197.6262793
predicted
DarkChem Lite v0.1.0
[M-H]-180.2934
predicted
DeepCCS 1.0 (2019)
[M+H]+197.9417793
predicted
DarkChem Lite v0.1.0
[M+H]+182.6514
predicted
DeepCCS 1.0 (2019)
[M+Na]+197.4102793
predicted
DarkChem Lite v0.1.0
[M+Na]+189.34523
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Receptor for endogenous opioids such as beta-endorphin and endomorphin (PubMed:10529478, PubMed:12589820, PubMed:7891175, PubMed:7905839, PubMed:7957926, PubMed:9689128). Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone (PubMed:10529478, PubMed:10836142, PubMed:12589820, PubMed:19300905, PubMed:7891175, PubMed:7905839, PubMed:7957926, PubMed:9689128). Also activated by enkephalin peptides, such as Met-enkephalin or Met-enkephalin-Arg-Phe, with higher affinity for Met-enkephalin-Arg-Phe (By similarity). 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 (PubMed:7905839). 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 extent to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15 (PubMed:12068084). 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 (By similarity). Also couples to adenylate cyclase stimulatory G alpha proteins (By similarity). The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4 (By similarity). Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization (By similarity). Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction (By similarity). The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins (By similarity). 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 (By similarity). 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 (By similarity). Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling (By similarity). Endogenous ligands induce rapid desensitization, endocytosis and recycling (By similarity). Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties (By similarity)
Specific Function
beta-endorphin receptor activity
Gene Name
OPRM1
Uniprot ID
P35372
Uniprot Name
Mu-type opioid receptor
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. [Article]
  2. 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. [Article]
  3. Tyers MB: A classification of opiate receptors that mediate antinociception in animals. Br J Pharmacol. 1980 Jul;69(3):503-12. [Article]
  4. 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. [Article]
  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. [Article]
  6. Bannwarth B, Richez C: The dextropropoxyphene controversy. Joint Bone Spine. 2009 Oct;76(5):449-51. doi: 10.1016/j.jbspin.2009.04.004. Epub 2009 Jul 14. [Article]
  7. Walker EA, Tiano MJ, Benyas SI, Dykstra LA, Picker MJ: Naltrexone and beta-funaltrexamine antagonism of the antinociceptive and response rate-decreasing effects of morphine, dezocine, and d-propoxyphene. Psychopharmacology (Berl). 1999 May;144(1):45-53. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
G-protein coupled receptor that functions as a 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
Specific Function
G protein-coupled enkephalin receptor activity
Gene Name
OPRD1
Uniprot ID
P41143
Uniprot Name
Delta-type opioid receptor
Molecular Weight
40368.235 Da
References
  1. Neil A: Affinities of some common opioid analgesics towards four binding sites in mouse brain. Naunyn Schmiedebergs Arch Pharmacol. 1984 Nov;328(1):24-9. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
G-protein coupled opioid receptor that functions as a receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as a 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
Specific Function
dynorphin receptor activity
Gene Name
OPRK1
Uniprot ID
P41145
Uniprot Name
Kappa-type opioid receptor
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. [Article]
  2. Neil A: Affinities of some common opioid analgesics towards four binding sites in mouse brain. Naunyn Schmiedebergs Arch Pharmacol. 1984 Nov;328(1):24-9. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs (PubMed:18762277, PubMed:7980644, PubMed:9169443, PubMed:9490062). Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acyl-CoA ester (PubMed:18762277, PubMed:7980644, PubMed:9169443, PubMed:9490062). Hydrolyzes the methyl ester group of cocaine to form benzoylecgonine (PubMed:7980644). Catalyzes the transesterification of cocaine to form cocaethylene (PubMed:7980644). Displays fatty acid ethyl ester synthase activity, catalyzing the ethyl esterification of oleic acid to ethyloleate (PubMed:7980644). Converts monoacylglycerides to free fatty acids and glycerol. Hydrolyzes of 2-arachidonoylglycerol and prostaglandins (PubMed:21049984). Hydrolyzes cellular cholesteryl esters to free cholesterols and promotes reverse cholesterol transport (RCT) by facilitating both the initial and final steps in the process (PubMed:11015575, PubMed:16024911, PubMed:16971496, PubMed:18762277). First of all, allows free cholesterol efflux from macrophages to extracellular cholesterol acceptors and secondly, releases free cholesterol from lipoprotein-delivered cholesteryl esters in the liver for bile acid synthesis or direct secretion into the bile (PubMed:16971496, PubMed:18599737, PubMed:18762277)
Specific Function
carboxylesterase activity
Gene Name
CES1
Uniprot ID
P23141
Uniprot Name
Liver carboxylesterase 1
Molecular Weight
62520.62 Da
References
  1. Zhang J, Burnell JC, Dumaual N, Bosron WF: Binding and hydrolysis of meperidine by human liver carboxylesterase hCE-1. J Pharmacol Exp Ther. 1999 Jul;290(1):314-8. [Article]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Component of NMDA receptor complexes that function as heterotetrameric, ligand-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Channel activation requires binding of the neurotransmitter glutamate to the epsilon subunit, glycine binding to the zeta subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+) (PubMed:26875626, PubMed:26919761, PubMed:28105280, PubMed:28126851, PubMed:7685113). Sensitivity to glutamate and channel kinetics depend on the subunit composition (PubMed:26919761)
Specific Function
amyloid-beta binding

Components:
References
  1. 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. doi: 10.1016/s0006-2952(98)00088-4. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
Specific Function
anandamide 11,12 epoxidase activity
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Yue QY, Sawe J: Different effects of inhibitors on the O- and N-demethylation of codeine in human liver microsomes. Eur J Clin Pharmacol. 1997;52(1):41-7. [Article]
  2. Kerry NL, Somogyi AA, Bochner F, Mikus G: The role of CYP2D6 in primary and secondary oxidative metabolism of dextromethorphan: in vitro studies using human liver microsomes. Br J Clin Pharmacol. 1994 Sep;38(3):243-8. [Article]
  3. Sanz EJ, Bertilsson L: d-Propoxyphene is a potent inhibitor of debrisoquine, but not S-mephenytoin 4-hydroxylation in vivo. Ther Drug Monit. 1990 May;12(3):297-9. doi: 10.1097/00007691-199005000-00016. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function
1,8-cineole 2-exo-monooxygenase activity
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Somogyi AA, Menelaou A, Fullston SV: CYP3A4 mediates dextropropoxyphene N-demethylation to nordextropropoxyphene: human in vitro and in vivo studies and lack of CYP2D6 involvement. Xenobiotica. 2004 Oct;34(10):875-87. doi: 10.1080/00498250400008371 . [Article]
  2. Spina E, Pisani F, Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clin Pharmacokinet. 1996 Sep;31(3):198-214. doi: 10.2165/00003088-199631030-00004. [Article]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function
1,8-cineole 2-exo-monooxygenase activity

Components:
References
  1. Yue QY, Sawe J: Different effects of inhibitors on the O- and N-demethylation of codeine in human liver microsomes. Eur J Clin Pharmacol. 1997;52(1):41-7. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:18719240, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:18719240, PubMed:23288867). Catalyzes the glucuronidation of the endogenous estrogen hormones such as estradiol and estriol (PubMed:18719240, PubMed:23288867)
Specific Function
glucuronosyltransferase activity
Gene Name
UGT2B4
Uniprot ID
P06133
Uniprot Name
UDP-glucuronosyltransferase 2B4
Molecular Weight
60512.035 Da
References
  1. Raungrut P, Uchaipichat V, Elliot DJ, Janchawee B, Somogyi AA, Miners JO: In vitro-in vivo extrapolation predicts drug-drug interactions arising from inhibition of codeine glucuronidation by dextropropoxyphene, fluconazole, ketoconazole, and methadone in humans. J Pharmacol Exp Ther. 2010 Aug;334(2):609-18. doi: 10.1124/jpet.110.167916. Epub 2010 May 18. [Article]

Drug created at June 13, 2005 13:24 / Updated at November 06, 2024 20:01