Loperamide
Overview
Description
Loperamide is a synthetic opioid receptor agonist primarily used as an anti-diarrheal agent. It was first synthesized in 1969 and introduced for medical use in 1976. This compound is commonly marketed under the brand name Imodium, among others. It is included in the World Health Organization’s List of Essential Medicines due to its effectiveness in treating various types of diarrhea, including acute nonspecific diarrhea, chronic diarrhea associated with inflammatory bowel disease, and traveler’s diarrhea .
Preparation Methods
Synthetic Routes and Reaction Conditions: The synthesis of loperamide involves multiple steps The resulting compound is then treated with a glacial acetic acid solution of hydrogen bromide to obtain 4-bro-2,2-dibenzylbutyric acidFinally, the compound reacts with 4-hydroxy-4-p-chlorophenylpiperidine to yield this compound .
Industrial Production Methods: Industrial production of this compound typically involves the direct compression or wet granulation processes to prepare tablets. These methods ensure the drug’s stability and bioavailability. Additionally, this compound can be formulated into solid lipid nanoparticles to enhance its oral absorption .
Chemical Reactions Analysis
Types of Reactions: Loperamide undergoes various chemical reactions, including ion-pair formation, oxidation, and reduction.
Common Reagents and Conditions:
Ion-Pair Formation: this compound hydrochloride forms an ion-pair association complex with rose Bengal, which can be analyzed spectrophotometrically.
Oxidation and Reduction: Specific conditions and reagents for oxidation and reduction reactions of this compound are not extensively documented, but these reactions are typical for compounds with similar structures.
Major Products: The major products formed from these reactions include ion-pair complexes and potentially oxidized or reduced derivatives of this compound.
Scientific Research Applications
Loperamide has a wide range of scientific research applications:
Mechanism of Action
Loperamide exerts its effects by binding to opioid receptors in the gut wall, specifically the mu-opioid receptors. This binding action inhibits the release of acetylcholine and prostaglandins, which are responsible for increasing gastrointestinal motility. As a result, this compound slows down intestinal contractions, allowing for increased absorption of fluids and electrolytes. This mechanism helps restore normal stool consistency and reduce the frequency of diarrhea .
Comparison with Similar Compounds
Diphenoxylate: Like loperamide, diphenoxylate is an opioid receptor agonist used to treat diarrhea.
Codeine: Codeine is another opioid with anti-diarrheal properties, but it is primarily used for its analgesic effects.
Haloperidol: Although not primarily an anti-diarrheal agent, haloperidol shares structural similarities with this compound.
Uniqueness of this compound: this compound’s uniqueness lies in its ability to effectively control diarrhea without significant central nervous system effects. Its low oral absorption and inability to cross the blood-brain barrier contribute to its safety profile, making it a preferred choice for managing diarrhea .
Properties
IUPAC Name |
4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C29H33ClN2O2/c1-31(2)27(33)29(24-9-5-3-6-10-24,25-11-7-4-8-12-25)19-22-32-20-17-28(34,18-21-32)23-13-15-26(30)16-14-23/h3-16,34H,17-22H2,1-2H3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
RDOIQAHITMMDAJ-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CN(C)C(=O)C(CCN1CCC(CC1)(C2=CC=C(C=C2)Cl)O)(C3=CC=CC=C3)C4=CC=CC=C4 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C29H33ClN2O2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Related CAS |
34552-83-5 (mono-hydrochloride) |
Source
|
| Record name | Loperamide [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0053179116 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
DSSTOX Substance ID |
DTXSID6045165 |
Source
|
| Record name | Loperamide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID6045165 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
477.0 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Loperamide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0004999 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Mechanism of Action |
Enteric neurons synthesize and release endogenous opioid peptides and other neurotransmitters, such as acetylcholine and substance P. Endogenous opioids bind to opioid receptors expressed on these neurons to regulate gastrointestinal signalling, motility, and balance of fluids and electrolytes. Loperamide acts on the mu-opioid receptor expressed on the circular and longitudinal intestinal muscle. Receptor binding leads to the recruitment of G-protein receptor kinases and the activation of downstream molecular cascades that inhibit enteric nerve activity. By inhibiting the excitability of enteric neurons, loperamide suppresses neurotransmitter release, pre-synaptic and post-synaptic inhibition of transmission of excitatory and inhibitory motor pathways, and secretomotor pathways. Loperamide inhibits the release of acetylcholine and prostaglandins, thereby reducing propulsive peristalsis and increasing intestinal transit time. Loperamide stimulates the intestinal absorption of water and electrolytes by inhibiting calmodulin. Loperamide can bind to and hyperpolarize submucosal secretomotor neurons, promoting dry, hard stools., ... The present study investigates the mechanism of the central analgesic effect of loperamide. Adult male Sprague-Dawley rats were subjected to surgery for catheter placement. Following baseline testing, different groups of rats were administered fixed intrathecal doses (1 ug, 3 ug, 10 ug and 30 ug) of loperamide and morphine. Analgesia was compared employing Hargreaves paw withdrawal apparatus at 15 min, 30 min, 60 min, 90 min and 120 min. Additionally, CTOP, a specific mu-opioid receptor antagonist was co-administered with loperamide to examine the mu-opioid receptor mediated loperamide analgesia. Furthermore, nefiracetam, a calcium channel opener, was co-administered with loperamide or morphine to evaluate the involvement of Ca(2+) channels in loperamide showed an analgesic effect which was comparable to morphine. However, loperamide produced longer analgesia and the analgesic effect was significantly better at 42 hr and 49 hr compared to morphine. CTOP completely reversed loperamide analgesia. Though nefiracetam significantly reversed loperamide analgesia, it did not have any effect on morphine induced analgesia. Our findings suggest that loperamide administered intrathecally produces analgesia which is mediated through mu-opioid receptor and subsequent blockade of downstream calcium channels., The effects of the antidiarrheal agent loperamide on high-voltage-activated (HVA) calcium channel activity and excitatory amino acid-evoked responses in two preparations of cultured hippocampal pyramidal neurons were examined. In rat hippocampal neurons loaded with the calcium-sensitive dye fura-2, rises in intracellular free calcium concentration ([Ca2+]i) evoked by transient exposure to 50 mM K(+)-containing medium [high extracellular potassium concentration ([K+]o)] were mediated by Ca2+ flux largely through nifedipine-sensitive Ca2+ channels, with smaller contributions from omega-conotoxin GVIA (omega-CgTx)-sensitive Ca2+ channels and channels insensitive to both nifedipine and omega-CgTx. Loperamide reversibly blocked rises in [Ca2+]i evoked by high [K+]o in a concentration-dependent manner, with an IC50 of 0.9 +/- 0.2 microM. At the highest concentration tested (50 microM), loperamide eliminated rises in [Ca2+]i evoked by high [K+]o, a result otherwise achieved only in Ca(2+)-free medium or by the combined application of nifedipine, omega-CgTx, and funnel web spider venom to Ca(2+)-containing medium. The action of loperamide was neither naloxone sensitive nor mimicked by morphine and was seen at concentrations substantially less than those required to block influx of Ca2+ through the N-methyl-D-aspartate (NMDA) receptor-operated ionophore. Similar results were obtained in cultured mouse hippocampal pyramidal neurons under whole-cell voltage clamp. Voltage-activated Ca2+ channel currents carried by barium ions (IBa) could be discriminated pharmacologically into nifedipine-sensitive (L-type) and nifedipine-resistant, omega-CgTx-sensitive (N-type) components. Loperamide (0.1-50 uM) produced a concentration-dependent reduction of the peak IBa with an IC50 value of 2.5 +/- 0.4 uM and, at the highest concentration tested, could fully block IBa in the absence of any other pharmacological agent. The loperamide-induced block was rapid in onset and offset, was fully reversible, and did not appear to be related to the known calmodulin antagonist actions of loperamide. The current-voltage characteristics of the whole-cell IBa were unaffected by loperamide and the block was not voltage dependent. Loperamide also attenuated NMDA-evoked currents recorded at a membrane potential of -60 mV, with an IC50 of 73 +/- 7 uM. The block of NMDA-evoked currents was not competitive in nature, was not reversed by elevation of the extracellular glycine or spermine concentration, and was not affected by changes in the membrane holding potential. Steady state currents evoked by kainate and DL-alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid were, in contrast, relatively unaffected by 100 microM loperamide., The intravenous injection of loperamide induced an immediate fall in blood pressure and heart rate in anesthetized rats. Both effects were inhibited by the opiate antagonists naloxone and MRZ 2266 BS. Bilateral vagotomy also inhibited both effects whereas atropine only reduced the bradycardia, but the combination of atropine and tertatolol suppressed the bradycardia. A high dose of loperamide induced bradycardia in pithed rats. This effect was prevented by MRZ 2266 BS but not by naloxone. It is concluded that loperamide can elicit a vagally mediated reflex involving vagal and sympathetic mechanisms and could stimulate cardiac opiate receptors, probably kappa, both effects leading to bradycardia., Motility in the gut is the result of cholinergic and noncholinergic biphasic stimulation of the intestinal musculature. The cholinergic mediator, acetylcholine (ACh), is responsible for the first phase of peristalsis, while prostaglandins (PG) are thought to mediate the second phase. Loperamide has been shown to inhibit release of both ACh and PG from isolated guinea pig ileum, as well as directly block the action of PG on smooth muscle preparations from rats. The net result is a reduction in the number of peristaltic waves, the fluid expelled by each wave, and overall gut motility. Loperamide produces a sustained inhibition of the peristaltic activity of the guinea pig ileum in vitro at doses as low as 0.005 mg/L. The inhibitory effects are dose-related, the activity of both the longitudinal and circular muscles being affected. At dose levels inhibiting peristaltic activity, loperamide antagonizes the spasmogenic effects of electrical- and nicotine-induced stimulation of this preparation. As well, the angiotensin-5- hydroxytryptamine-, bradykinin-barium chloride- and histamine-induced contractions of the guinea pig ileum preparation are inhibited by doses of 0.14 mg/L or more. On the other hand, loperamide is inactive against 5-hydroxytryptamine on the rat fundus, epinephrine on the rabbit spleen, acetylcholine on the rabbit duodenum and isoproterenol on the hen rectal caecum preparations at dose levels of up to 10 mg/L. A moderate negative inotropic effect is produced on the cat papillary muscle at 3 and 10 mg/L, and a moderate negative chronotropic effect is produced on the guinea pig atrium at 0.16 mg/L. This antagonism is thought to be unspecific. |
Source
|
| Record name | Loperamide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00836 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Loperamide | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8344 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
CAS No. |
53179-11-6 |
Source
|
| Record name | Loperamide | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=53179-11-6 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Loperamide [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0053179116 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Loperamide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00836 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Loperamide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID6045165 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Loperamide | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.053.088 | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | LOPERAMIDE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/6X9OC3H4II | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
| Record name | Loperamide | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8344 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Loperamide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0004999 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Melting Point |
220-228 |
Source
|
| Record name | Loperamide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00836 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
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