molecular formula C29H34Cl2N2O2 B1675071 Loperamide hydrochloride CAS No. 34552-83-5

Loperamide hydrochloride

Cat. No.: B1675071
CAS No.: 34552-83-5
M. Wt: 513.5 g/mol
InChI Key: PGYPOBZJRVSMDS-UHFFFAOYSA-N
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Mechanism of Action

Target of Action

Loperamide hydrochloride primarily targets the mu-opioid receptors in the myenteric plexus of the large intestine . These receptors play a crucial role in regulating intestinal motility and fluid secretion .

Mode of Action

This compound acts as an agonist at the mu-opioid receptors . By binding to these receptors, it decreases the activity of the myenteric plexus, which in turn reduces the tone of the longitudinal and circular smooth muscles of the intestinal wall . This action slows down the contractions of the intestines .

Biochemical Pathways

The primary metabolic pathway of this compound involves oxidative N-demethylation, mediated by CYP2C8 and CYP3A4 enzymes . This process forms N-demethyl loperamide, which is pharmacologically inactive . CYP2B6 and CYP2D6 also play a minor role in loperamide N-demethylation .

Pharmacokinetics

This compound is a highly lipophilic synthetic phenylpiperidine opioid . It is extensively metabolized in the liver . The bioavailability of this compound is low (0.3%) due to extensive first-pass metabolism . The elimination half-life of this compound is approximately 9-14 hours , and it is excreted primarily in the feces (30-40%) and to a lesser extent in the urine (1%) .

Result of Action

The action of this compound results in a decrease in intestinal motility and fluid secretion . This leads to an increase in the time for fluids and nutrients to be absorbed back into the body, which makes the stool less watery and decreases the frequency of bowel movements .

Safety and Hazards

Loperamide hydrochloride should be used with caution. Avoid breathing mist, gas or vapours. Avoid contacting with skin and eye. Use personal protective equipment. Wear chemical impermeable gloves. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe areas. Keep people away from and upwind of spill/leak .

Biochemical Analysis

Biochemical Properties

Loperamide hydrochloride plays a significant role in biochemical reactions by interacting with various enzymes, proteins, and other biomolecules. It primarily binds to the mu-opioid receptors located on the circular and longitudinal intestinal muscles . This binding leads to the recruitment of G-protein receptor kinases and the activation of downstream molecular cascades that inhibit enteric nerve activity . Additionally, this compound affects water and electrolyte movement through the bowel, thereby reducing propulsive peristalsis and increasing intestinal transit time .

Cellular Effects

This compound exerts several effects on different types of cells and cellular processes. It influences cell function by inhibiting the excitability of enteric neurons, which suppresses gastrointestinal motility . This compound also affects cell signaling pathways by binding to the mu-opioid receptors and activating G-protein coupled receptor pathways . Furthermore, this compound impacts gene expression and cellular metabolism by modulating the release of neurotransmitters such as acetylcholine and prostaglandins .

Molecular Mechanism

The molecular mechanism of this compound involves its action on the mu-opioid receptors in the gut. By binding to these receptors, this compound inhibits the release of acetylcholine and prostaglandins, which reduces propulsive peristalsis and increases intestinal transit time . This compound also increases the tone of the anal sphincter, thereby reducing incontinence and urgency . The binding interactions with biomolecules and enzyme inhibition play a crucial role in its antidiarrheal effects .

Temporal Effects in Laboratory Settings

In laboratory settings, the effects of this compound change over time. Studies have shown that this compound is stable and maintains its efficacy in controlling diarrhea over extended periods . Higher than recommended dosages can lead to life-threatening cardiac, central nervous system, and respiratory adverse reactions . Long-term effects on cellular function include the potential for cardiac arrhythmias and other serious adverse effects .

Dosage Effects in Animal Models

The effects of this compound vary with different dosages in animal models. At therapeutic doses, it effectively controls diarrhea without significant adverse effects . At higher doses, this compound can induce neurotoxic effects, including psychosis-like behaviors in mice . Additionally, high doses can lead to cardiac toxicity and other severe adverse effects .

Metabolic Pathways

This compound is primarily metabolized in the liver through oxidative N-demethylation mediated by cytochrome P450 enzymes, specifically CYP2C8 and CYP3A4 . The metabolites of this compound are pharmacologically inactive and are excreted via the bile . This metabolic pathway ensures the efficient clearance of the compound from the body .

Transport and Distribution

This compound is transported and distributed within cells and tissues primarily through plasma protein binding. Approximately 95% of this compound is bound to plasma proteins . It is also a substrate for P-glycoprotein, which limits its penetration across the blood-brain barrier . This transport mechanism ensures that this compound remains localized in the gut, where it exerts its therapeutic effects .

Subcellular Localization

The subcellular localization of this compound is primarily within the gut wall, where it binds to the mu-opioid receptors . This localization is facilitated by its high lipophilicity and affinity for the receptors in the intestinal muscles . The compound’s activity and function are directed towards reducing gastrointestinal motility and increasing intestinal transit time .

Preparation Methods

Synthetic Routes and Reaction Conditions: Loperamide hydrochloride is synthesized through a multi-step process involving the reaction of 4-chlorobenzhydryl chloride with 4-hydroxypiperidine to form 4-(4-chlorophenyl)-4-hydroxypiperidine. This intermediate is then reacted with N,N-dimethyl-2,2-diphenylbutanamide to yield loperamide .

Industrial Production Methods: In industrial settings, this compound is produced using high-pressure liquid chromatography (HPLC) for purification. The process involves potentiometric titration and the use of mobile phases containing potassium phosphate monobasic and acetonitrile .

Chemical Reactions Analysis

Types of Reactions: Loperamide hydrochloride undergoes various chemical reactions, including:

Common Reagents and Conditions:

Major Products Formed:

Comparison with Similar Compounds

Uniqueness: this compound is unique due to its high affinity for peripheral opioid receptors and minimal central nervous system penetration, which reduces the risk of central opioid effects such as euphoria and dependence .

Properties

IUPAC Name

4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide;hydrochloride
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

InChI

InChI=1S/C29H33ClN2O2.ClH/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;1H
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

InChI Key

PGYPOBZJRVSMDS-UHFFFAOYSA-N
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.Cl
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Molecular Formula

C29H34Cl2N2O2
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Related CAS

53179-11-6 (Parent)
Record name Loperamide hydrochloride [USAN:USP:JAN]
Source ChemIDplus
URL https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0034552835
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

DTXSID00880006
Record name 4-(4-Chlorophenyl)-4-hydroxy-N,N-dimethyl-alpha,alpha-diphenylpiperidine-1-butyramide monohydrochloride
Source EPA DSSTox
URL https://comptox.epa.gov/dashboard/DTXSID00880006
Description DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.

Molecular Weight

513.5 g/mol
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Solubility

>77 [ug/mL] (The mean of the results at pH 7.4)
Record name SID11533030
Source Burnham Center for Chemical Genomics
URL https://pubchem.ncbi.nlm.nih.gov/bioassay/1996#section=Data-Table
Description Aqueous solubility in buffer at pH 7.4

CAS No.

34552-83-5
Record name Loperamide hydrochloride
Source CAS Common Chemistry
URL https://commonchemistry.cas.org/detail?cas_rn=34552-83-5
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 hydrochloride [USAN:USP:JAN]
Source ChemIDplus
URL https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0034552835
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 hydrochloride
Source DTP/NCI
URL https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=759568
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Explanation Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
Record name 4-(4-Chlorophenyl)-4-hydroxy-N,N-dimethyl-alpha,alpha-diphenylpiperidine-1-butyramide monohydrochloride
Source EPA DSSTox
URL https://comptox.epa.gov/dashboard/DTXSID00880006
Description DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.
Record name 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenylpiperidine-1-butyramide monohydrochloride
Source European Chemicals Agency (ECHA)
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Record name LOPERAMIDE HYDROCHLORIDE
Source FDA Global Substance Registration System (GSRS)
URL https://gsrs.ncats.nih.gov/ginas/app/beta/substances/77TI35393C
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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.

Retrosynthesis Analysis

AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.

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Strategy Settings

Precursor scoring Relevance Heuristic
Min. plausibility 0.01
Model Template_relevance
Template Set Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis
Top-N result to add to graph 6

Feasible Synthetic Routes

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