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Record Information
Version2.0
Creation Date2009-07-21 20:28:19 UTC
Update Date2014-12-24 20:25:54 UTC
Accession NumberT3D2978
Identification
Common NameDiphenoxylate
ClassSmall Molecule
DescriptionA meperidine congener used as an antidiarrheal, usually in combination with atropine. At high doses, it acts like morphine. Its unesterified metabolite difenoxin has similar properties and is used similarly. It has little or no analgesic activity. This medication is classified as a Schedule V under the Controlled Substances Act by the Food and Drug Administration (FDA) and the DEA in the United States when used in preparations. When diphenoxylate is used alone, it is classified as a Schedule II.
Compound Type
  • Amine
  • Analgesic, Opioid
  • Antidiarrheal
  • Antiperistaltic Agent
  • Drug
  • Ester
  • Ether
  • Food Toxin
  • Metabolite
  • Narcotic
  • Nitrile
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
1-(3-Cyano-3,3-diphenylpropyl)-4-phenyl-isonipecotic acid ethyl ester
2,2-Diphenyl-4-(4-carbethoxy-4-phenylpiperidino)butyronitrile
4-Ethoxycarbonyl-alpha,alpha,4-triphenyl-1-piperidinebutyronitrile
Dea No. 9170
Difenossilato
Difenoxilato
Diphenoxalate
Diphenoxylatum
Diphenoxylic acid
Ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxylate
Ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylisonipecotate
Lomotil
Chemical FormulaC30H32N2O2
Average Molecular Mass452.587 g/mol
Monoisotopic Mass452.246 g/mol
CAS Registry Number915-30-0
IUPAC Nameethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate
Traditional Namediphenoxylate
SMILESCCOC(=O)C1(CCN(CCC(C#N)(C2=CC=CC=C2)C2=CC=CC=C2)CC1)C1=CC=CC=C1
InChI IdentifierInChI=1S/C30H32N2O2/c1-2-34-28(33)29(25-12-6-3-7-13-25)18-21-32(22-19-29)23-20-30(24-31,26-14-8-4-9-15-26)27-16-10-5-11-17-27/h3-17H,2,18-23H2,1H3
InChI KeyInChIKey=HYPPXZBJBPSRLK-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as diphenylacetonitriles. These are cyclic aromatic compounds containing a diphenylacetonitrile moiety, which consists of a diphenylmethane linked to and acetonitrile to form 2,2-diphenylacetonitrile.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassDiphenylacetonitriles
Direct ParentDiphenylacetonitriles
Alternative Parents
Substituents
  • Diphenylacetonitrile
  • Diphenylmethane
  • Phenylpiperidine
  • Piperidinecarboxylic acid
  • Aralkylamine
  • Piperidine
  • Amino acid or derivatives
  • Carboxylic acid ester
  • Tertiary amine
  • Tertiary aliphatic amine
  • Nitrile
  • Carbonitrile
  • Monocarboxylic acid or derivatives
  • Carboxylic acid derivative
  • Organoheterocyclic compound
  • Azacycle
  • Hydrocarbon derivative
  • Organic oxide
  • Amine
  • Organooxygen compound
  • Organonitrogen compound
  • Organic oxygen compound
  • Organic nitrogen compound
  • Organopnictogen compound
  • Carbonyl group
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point220.5-222°C
Boiling PointNot Available
Solubility800 mg/L (at 25°C)
LogP6.3
Predicted Properties
PropertyValueSource
Water Solubility0.0015 g/LALOGPS
logP5.74ALOGPS
logP5.88ChemAxon
logS-5.5ALOGPS
pKa (Strongest Basic)8.5ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area53.33 ŲChemAxon
Rotatable Bond Count9ChemAxon
Refractivity146.76 m³·mol⁻¹ChemAxon
Polarizability51.58 ųChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0002-6591000000-e04da61bbde263b104e32017-09-12View Spectrum
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0002-6591000000-e04da61bbde263b104e32018-05-18View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-004i-1129000000-033454565afde0495c582017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0udi-0000900000-e2841fe11576faaa404e2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0udi-0000900000-f16aa8a859221ed0173c2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0udi-0220900000-38d21080081c6d1444982017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0ap0-2920000000-ed4957b090e4b3a6f38d2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0aor-2900000000-becb90ead622a0131fdb2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0udi-0210900000-f33819852c9168d0f8a02017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 40V, Positivesplash10-0ap0-2930000000-27b1d68dee5988eaa1352021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 30V, Positivesplash10-0udi-0220900000-eb48236d047d8482c9db2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 10V, Positivesplash10-0udi-0000900000-e2841fe11576faaa404e2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 20V, Positivesplash10-0udi-0000900000-f16aa8a859221ed0173c2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 35V, Positivesplash10-0ufr-1222900000-c125937f2ff3621120702021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 50V, Positivesplash10-0aor-2900000000-b973c5ffabd9b4d287ca2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 50V, Positivesplash10-0aor-2900000000-5fa40194a7aea2fbeaff2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 30V, Positivesplash10-0udi-0220900000-38d21080081c6d1444982021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 40V, Positivesplash10-0ap0-2920000000-ed4957b090e4b3a6f38d2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 50V, Positivesplash10-0aor-2900000000-becb90ead622a0131fdb2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 40V, Positivesplash10-0ap0-2930000000-315293eb975bc2a18e682021-09-20View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0udi-0011900000-4f997e63c9c65b9c3cf32016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-05g0-0344900000-56fc8f46c973ef960e512016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-00di-0971000000-b83c6e7e52cb3ee497b02016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0udi-0000900000-ec078fed32982bfba96e2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0ufr-2343900000-eaa7ee09954f3184115d2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-116u-3941000000-217be57f7c4a4f20f18a2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0udi-0003900000-ed80455eb1b0d171468d2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0ugi-0009100000-945c8f0ee309cb0cc7df2021-10-11View Spectrum
MSMass Spectrum (Electron Ionization)splash10-0002-2390000000-0d133bb29f340639db022014-09-20View Spectrum
Toxicity Profile
Route of ExposureOral. 90%
Mechanism of ToxicityDiphenoxylate is an opiate receptor agonists that stimulate mu receptors in GI to decrease the peristalsis and constrict the sphincters. Diphenoxylate has a direct effect on circular smooth muscle of the bowel, that conceivably results in segmentation and prolongation of gastrointestinal transit time. The clinical antidiarrheal action of diphenoxylate may thus be a consequence of enhanced segmentation that allows increased contact of the intraluminal contents with the intestinal mucosa.
MetabolismHepatic Half Life: 12-14 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor as adjunctive therapy in the management of diarrhea
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, dry skin and mucous membranes, enlarged pupils of the eyes, extremely high body temperature, flushing, involuntary eyeball movement, lower than normal muscle tone, pinpoint pupils, rapid heartbeat, restlessness, sluggishness, suppressed breathing
TreatmentIn the event of overdose, induction of vomiting, gastric lavage, establishment of a patent airway, and possibly mechanically assisted respiration are advised. in vitro and animal studies indicate that activated charcoal may significantly decrease the bioavailability of diphenoxylate. In noncomatose patients, a slurry of 100 g of activated charcoal can be administered immediately after the induction of vomiting or gastric lavage. A pure narcotic antagonist (eg, naloxone) should be used in the treatment of respiratory depression caused by Lomotil. When a narcotic antagonist is administered intravenously, the onset of action is generally apparent within two minutes. It may also be administered subcutaneously or intramuscularly, providing a slightly less rapid onset of action but a more prolonged effect. (2)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01081
HMDB IDHMDB15213
PubChem Compound ID13505
ChEMBL IDCHEMBL1201294
ChemSpider ID12919
KEGG IDC07872
UniProt IDNot Available
OMIM ID
ChEBI ID4639
BioCyc IDNot Available
CTD IDNot Available
Stitch IDDiphenoxylate
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkDiphenoxylate
References
Synthesis Reference

Janssen, P.A.J.; U.S.Patent 2,898,340; August 4,1959.
Dryden, H.L. Jr. and Erickson, R.A.; U.S. Patent 4,086,234; April 25,1978; assigned to
G.D.Searle & Co.

MSDSLink
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. 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. Coupar IM: The peristaltic reflex in the rat ileum: evidence for functional mu- and delta-opiate receptors. J Pharm Pharmacol. 1995 Aug;47(8):643-6. [8583364 ]
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. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
General Function:
Voltage-gated ion channel activity
Specific Function:
Mediates the voltage-dependent potassium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a potassium-selective channel through which potassium ions may pass in accordance with their electrochemical gradient.
Gene Name:
KCNA3
Uniprot ID:
P22001
Molecular Weight:
63841.09 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC505 uMNot AvailableBindingDB 50401672
References
  1. Nguyen W, Howard BL, Jenkins DP, Wulff H, Thompson PE, Manallack DT: Structure-activity relationship exploration of Kv1.3 blockers based on diphenoxylate. Bioorg Med Chem Lett. 2012 Dec 1;22(23):7106-9. doi: 10.1016/j.bmcl.2012.09.080. Epub 2012 Sep 29. [23084278 ]