Page last updated: 2024-12-05

diphenoxylate

Description Research Excerpts Clinical Trials Roles Classes Pathways Study Profile Bioassays Related Drugs Related Conditions Protein Interactions Research Growth Market Indicators

Description

Diphenoxylate is an opioid antidiarrheal medication. It is a synthetic derivative of meperidine and is structurally similar to methadone. Diphenoxylate is an agonist of the μ-opioid receptor and its primary effect is to slow the motility of the gastrointestinal tract. It is commonly used in combination with atropine, which helps to prevent the adverse effects of diphenoxylate, such as sedation and euphoria. Diphenoxylate is typically used to treat acute diarrhea, although it is also used for chronic diarrhea in some cases. Diphenoxylate is available by prescription only. The synthesis of diphenoxylate involves a multi-step process that starts with the reaction of ethyl 4-phenyl-4-piperidinecarboxylate with 1-chloro-2-diethylaminoethane. The resulting intermediate is then reacted with diphenylacetic acid to produce diphenoxylate. Diphenoxylate is studied to understand its mechanism of action, to develop new and improved antidiarrheal medications, and to explore its potential therapeutic uses in other conditions, such as irritable bowel syndrome. Diphenoxylate is an important medication for the treatment of diarrhea and it is frequently used by healthcare professionals.'

Diphenoxylate: A 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. [Medical Subject Headings (MeSH), National Library of Medicine, extracted Dec-2023]

diphenoxylate : A piperidinecarboxylate ester that is the ethyl ester of difenoxin. [Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]

Cross-References

ID SourceID
PubMed CID13505
CHEMBL ID1201294
CHEBI ID4639
SCHEMBL ID42940
MeSH IDM0006512

Synonyms (59)

Synonym
5-22-02-00487 (beilstein handbook reference)
unii-73312p173g
nih 7562
difenossilato
73312p173g ,
ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate
isonipecotic acid, 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-, ethyl ester
difenossilato [dcit]
r-1132
hsdb 3067
difenoxilato [spanish]
difenoxilato [inn-spanish]
diphenoxylatum [latin]
lomotil
diphenoxylate [inn:ban]
1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxylic acid ethyl ester
brn 0503374
diphenoxylatum [inn-latin]
einecs 213-020-1
dea no. 9170
4-piperidinecarboxylic acid, 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-, ethyl ester
diphenoxylate
C07872
915-30-0
ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylisonipecotate
1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-isonipecotic acid ethyl ester
DB01081
ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxylate
2,2-diphenyl-4-(4-carbethoxy-4-phenylpiperidino)butyronitrile
NCGC00167963-01
L001046
D07861
diphenoxylate (inn)
AKOS005065925
NCGC00167963-02
ids-nd-016
CHEMBL1201294
4-ethoxycarbonyl-alpha,alpha,4-triphenyl-1-piperidinebutyronitrile
diphenoxylatum
CHEBI:4639 ,
difenoxilato
diphenoxalate
bdbm50401672
1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid ethyl ester
diphenoxylate [hsdb]
diphenoxylate [vandf]
diphenoxylate [inn]
diphenoxylate [who-dd]
diphenoxylate [mi]
gtpl7164
co-phenotrope
AB00698456-07
SCHEMBL42940
HYPPXZBJBPSRLK-UHFFFAOYSA-N
ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxylate #
ethyl-1-(3-cyano-3,3-diphenylpropyl)-4-phenylisonipecotate
DTXSID8022951
diphenoxylate; diphenoxylate hydrochloride; ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate
Q416431

Research Excerpts

Treatment

ExcerptReferenceRelevance
"The diphenoxylate treatment lengthened the transit time of the barium sulphate to caecum from 3.2 to 4.3 h."( An X-ray study on the acute action of diphenoxylate on the intestinal motility in volunteers.
Anttila, P; Gothoni, G; Laasonen, L; Svinhufvud, U; Ylitalo, P, 1975
)
1.01

Bioavailability

ExcerptReferenceRelevance
" Activated charcoal modified the bioavailability of diphenoxylate hydrochloride in vivo."( In vitro adsorption of diphenoxylate hydrochloride on activated charcoal and its relationship to pharmacological effects of drug in vivo. I.
Dahani, EZ; Sanvordeker, DR, 1975
)
0.82

Dosage Studied

ExcerptRelevanceReference
" No side effect were observed at the therapeutic dosage level, and the drug was well accepted by subjects."( Use of difenoximide (SC-26100) for narcotic detoxification: a preliminary tolerance and efficacy study.
Dobrin, EI; Krantz, KD; Tennant, FS, 1977
)
0.26
" These results suggest that codeine phosphate has a beneficial effect on ileostomy function, reducing the loss of water and electrolytes, while Lomotil has a similar but less effective action in the dosage tested."( Effect of codeine phosphate, Lomotil, and Isogel on iileostomy function.
Newton, CR, 1978
)
0.26
" The dosage of 15-methyl-PGF2a was 200 mcg, then 300 mcg every 3 hours for up to 30 hours."( Prostaglandins and abortion. I. intramuscular administration of 15-methyl prostaglandin F2alpha for induction of abortion in weeks 10 to 20 of pregnancy. World Health Organization Task Force on the Use of Prostaglandins for the Regulation of Fertility.
, 1977
)
0.26
" By 24 hr after dosing plasma levls had decreased to 14."( The evaluation and application of a radioimmunoassay for the measurement of diphenoxylic acid, the major metabolite of diphenoxylate hydrochloride (Lomotil), in human plasma.
Jackson, LS; Stafford, JE, 1987
)
0.48
[information is derived through text-mining from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Roles (1)

RoleDescription
antidiarrhoeal drugAny drug found useful in the symptomatic treatment of diarrhoea.
[role information is derived from Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]

Drug Classes (4)

ClassDescription
nitrileA compound having the structure RC#N; thus a C-substituted derivative of hydrocyanic acid, HC#N. In systematic nomenclature, the suffix nitrile denotes the triply bound #N atom, not the carbon atom attached to it.
piperidinecarboxylate ester
tertiary amineA compound formally derived from ammonia by replacing three hydrogen atoms by hydrocarbyl groups.
ethyl esterAny carboxylic ester resulting from the formal condensation of the carboxy group of a carboxylic acid with ethanol.
[compound class information is derived from Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]

Pathways (1)

PathwayProteinsCompounds
Diphenoxylate Action Pathway3111

Protein Targets (6)

Potency Measurements

ProteinTaxonomyMeasurementAverage (µ)Min (ref.)Avg (ref.)Max (ref.)Bioassay(s)
USP1 protein, partialHomo sapiens (human)Potency4.46680.031637.5844354.8130AID504865
euchromatic histone-lysine N-methyltransferase 2Homo sapiens (human)Potency0.70790.035520.977089.1251AID504332
gemininHomo sapiens (human)Potency12.76060.004611.374133.4983AID624296; AID624297
peripheral myelin protein 22Rattus norvegicus (Norway rat)Potency18.10560.005612.367736.1254AID624032
[prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023]

Inhibition Measurements

ProteinTaxonomyMeasurementAverageMin (ref.)Avg (ref.)Max (ref.)Bioassay(s)
Potassium voltage-gated channel subfamily A member 3Homo sapiens (human)IC50 (µMol)5.00000.00203.19698.0000AID717088
Mu-type opioid receptorHomo sapiens (human)Ki0.01240.00000.419710.0000AID1823673
[prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023]

Biological Processes (22)

Processvia Protein(s)Taxonomy
potassium ion transportPotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
optic nerve developmentPotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
corpus callosum developmentPotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
protein homooligomerizationPotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
action potentialPotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
potassium ion transmembrane transportPotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messengerMu-type opioid receptorHomo sapiens (human)
adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathwayMu-type opioid receptorHomo sapiens (human)
phospholipase C-activating G protein-coupled receptor signaling pathwayMu-type opioid receptorHomo sapiens (human)
sensory perceptionMu-type opioid receptorHomo sapiens (human)
negative regulation of cell population proliferationMu-type opioid receptorHomo sapiens (human)
sensory perception of painMu-type opioid receptorHomo sapiens (human)
G protein-coupled opioid receptor signaling pathwayMu-type opioid receptorHomo sapiens (human)
behavioral response to ethanolMu-type opioid receptorHomo sapiens (human)
positive regulation of neurogenesisMu-type opioid receptorHomo sapiens (human)
negative regulation of Wnt protein secretionMu-type opioid receptorHomo sapiens (human)
positive regulation of ERK1 and ERK2 cascadeMu-type opioid receptorHomo sapiens (human)
calcium ion transmembrane transportMu-type opioid receptorHomo sapiens (human)
cellular response to morphineMu-type opioid receptorHomo sapiens (human)
regulation of cellular response to stressMu-type opioid receptorHomo sapiens (human)
regulation of NMDA receptor activityMu-type opioid receptorHomo sapiens (human)
neuropeptide signaling pathwayMu-type opioid receptorHomo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Molecular Functions (11)

Processvia Protein(s)Taxonomy
voltage-gated monoatomic ion channel activityPotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
protein bindingPotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
outward rectifier potassium channel activityPotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
delayed rectifier potassium channel activityPotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
G-protein alpha-subunit bindingMu-type opioid receptorHomo sapiens (human)
G protein-coupled receptor activityMu-type opioid receptorHomo sapiens (human)
beta-endorphin receptor activityMu-type opioid receptorHomo sapiens (human)
voltage-gated calcium channel activityMu-type opioid receptorHomo sapiens (human)
protein bindingMu-type opioid receptorHomo sapiens (human)
morphine receptor activityMu-type opioid receptorHomo sapiens (human)
G-protein beta-subunit bindingMu-type opioid receptorHomo sapiens (human)
neuropeptide bindingMu-type opioid receptorHomo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Ceullar Components (16)

Processvia Protein(s)Taxonomy
plasma membranePotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
presynaptic membranePotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
calyx of HeldPotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
membrane raftPotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
postsynaptic membranePotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
glutamatergic synapsePotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
voltage-gated potassium channel complexPotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
axonPotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
membranePotassium voltage-gated channel subfamily A member 3Homo sapiens (human)
endosomeMu-type opioid receptorHomo sapiens (human)
endoplasmic reticulumMu-type opioid receptorHomo sapiens (human)
Golgi apparatusMu-type opioid receptorHomo sapiens (human)
plasma membraneMu-type opioid receptorHomo sapiens (human)
axonMu-type opioid receptorHomo sapiens (human)
dendriteMu-type opioid receptorHomo sapiens (human)
perikaryonMu-type opioid receptorHomo sapiens (human)
synapseMu-type opioid receptorHomo sapiens (human)
plasma membraneMu-type opioid receptorHomo sapiens (human)
neuron projectionMu-type opioid receptorHomo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Bioassays (7)

Assay IDTitleYearJournalArticle
AID504749qHTS profiling for inhibitors of Plasmodium falciparum proliferation2011Science (New York, N.Y.), Aug-05, Volume: 333, Issue:6043
Chemical genomic profiling for antimalarial therapies, response signatures, and molecular targets.
AID1149212Antidiarrheal activity in Charles River rat assessed as inhibition of castor oil-induced diarrhea by measuring protected animals at 0.2 mg/kg, po administered for 5 days followed by 0.2 mg/kg, po on test day administered 1 hr prior to castor oil challenge1976Journal of medicinal chemistry, Apr, Volume: 19, Issue:4
Drugs derived from cannabinoids. 5. delta6a,10a-Tetrahydrocannabinol and heterocyclic analogs containing aromatic side chains.
AID1474166Liver toxicity in human assessed as induction of drug-induced liver injury by measuring severity class index2016Drug discovery today, Apr, Volume: 21, Issue:4
DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans.
AID1823673Displacement of [3H]DAMGO from human mu opioid receptor expressed in HEK293 cell membrane incubated for 60 mins by radioligand binding assay
AID1474167Liver toxicity in human assessed as induction of drug-induced liver injury by measuring verified drug-induced liver injury concern status2016Drug discovery today, Apr, Volume: 21, Issue:4
DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans.
AID717088Inhibition of Kv1.3 expressed in mouse L929 cells exposed to depolarizing step pulses from -80 mV to +40 mV by whole cell patch clamp method2012Bioorganic & medicinal chemistry letters, Dec-01, Volume: 22, Issue:23
Structure-activity relationship exploration of Kv1.3 blockers based on diphenoxylate.
AID1159607Screen for inhibitors of RMI FANCM (MM2) intereaction2016Journal of biomolecular screening, Jul, Volume: 21, Issue:6
A High-Throughput Screening Strategy to Identify Protein-Protein Interaction Inhibitors That Block the Fanconi Anemia DNA Repair Pathway.
[information is prepared from bioassay data collected from National Library of Medicine (NLM), extracted Dec-2023]

Research

Studies (223)

TimeframeStudies, This Drug (%)All Drugs %
pre-1990165 (73.99)18.7374
1990's17 (7.62)18.2507
2000's12 (5.38)29.6817
2010's20 (8.97)24.3611
2020's9 (4.04)2.80
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Market Indicators

Research Demand Index: 87.61

According to the monthly volume, diversity, and competition of internet searches for this compound, as well the volume and growth of publications, there is estimated to be very strong demand-to-supply ratio for research on this compound.

MetricThis Compound (vs All)
Research Demand Index87.61 (24.57)
Research Supply Index5.61 (2.92)
Research Growth Index4.55 (4.65)
Search Engine Demand Index156.07 (26.88)
Search Engine Supply Index2.00 (0.95)

This Compound (87.61)

All Compounds (24.57)

Study Types

Publication TypeThis drug (%)All Drugs (%)
Trials31 (12.81%)5.53%
Reviews17 (7.02%)6.00%
Case Studies38 (15.70%)4.05%
Observational0 (0.00%)0.25%
Other156 (64.46%)84.16%
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Clinical Trials (1)

Trial Overview

TrialPhaseEnrollmentStudy TypeStart DateStatus
An Open Label Study to Characterize the Incidence and Severity of Diarrhea in Patients With HER2+ Breast Cancer Treated With Neratinib With or Without Trastuzumab [NCT03094052]Phase 211 participants (Actual)Interventional2018-10-09Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

Trial Outcomes

TrialOutcome
NCT03094052 (6) [back to overview]Number of Participants Who Discontinued Neratinib Early
NCT03094052 (6) [back to overview]Number of Participants With Neratinib Dose Holds
NCT03094052 (6) [back to overview]Number of Participants With Neratinib Dose-reductions
NCT03094052 (6) [back to overview]Percentage of Participants With Grade 3 or Greater Diarrhea
NCT03094052 (6) [back to overview]Percentage of Participants With Multiple Anti-diarrheal Medications
NCT03094052 (6) [back to overview]Percentage of Participants With Treatment-related Adverse Events

Number of Participants Who Discontinued Neratinib Early

The number of participants who discontinued neratinib earlier than expected during the course of study therapy will be reported (NCT03094052)
Timeframe: Up to 55 weeks

InterventionParticipants (Count of Participants)
Treatment (Neratinib)1

[back to top]

Number of Participants With Neratinib Dose Holds

The number of participants who experienced a dose hold of neratinib during the course of study therapy will be reported (NCT03094052)
Timeframe: Up to 55 weeks

InterventionParticipants (Count of Participants)
Treatment (Neratinib)0

[back to top]

Number of Participants With Neratinib Dose-reductions

The number of participants whose dose was reduced at any time during the course of therapy will be reported (NCT03094052)
Timeframe: Up to 55 weeks

InterventionParticipants (Count of Participants)
Treatment (Neratinib)5

[back to top]

Percentage of Participants With Grade 3 or Greater Diarrhea

Percentage of participants with clinically assessed grade 3 or greater diarrhea reported within the first 2 cycles (each cycle is 21 days) of neratinib while using anti-diarrheal strategies. Reports of diarrhea will be graded according to NCI CTCAE version 4.0. (NCT03094052)
Timeframe: Up to 6 weeks

Interventionpercentage of participants (Number)
Treatment (Neratinib)36.3

[back to top]

Percentage of Participants With Multiple Anti-diarrheal Medications

Percentage of patients requiring multiple anti-diarrheal medications will be reported (NCT03094052)
Timeframe: Up to 55 weeks

InterventionParticipants (Count of Participants)
Treatment (Neratinib)7

[back to top] [back to top]