Loperamide

Opioid Receptor Agonism

Loperamide functions as an agonist at opioid receptors, with a particular affinity for mu-opioid receptors (MORs) located within the gastrointestinal tract. drugbank.comfrontiersin.orgwikipedia.orgpatsnap.com

This compound selectively binds to mu (μ)-opioid receptors present on both the circular and longitudinal intestinal muscles. drugbank.comfrontiersin.orgwikipedia.orgpatsnap.com This binding initiates a series of intracellular events, including the recruitment of G-protein receptor kinases and the activation of downstream molecular cascades, which collectively inhibit enteric nerve activity. drugbank.com

The agonism of MORs by this compound leads to a significant decrease in the activity of the myenteric plexus, a crucial component of the enteric nervous system responsible for coordinating gastrointestinal motility. frontiersin.orgwikipedia.orgpatsnap.comresearchgate.neted.ac.ukkoreamed.orgfrontiersin.org This modulation of myenteric plexus activity subsequently reduces the tone of both the longitudinal and circular smooth muscles of the intestine, thereby inhibiting propulsive peristaltic movements. frontiersin.orgwikipedia.orgpatsnap.comresearchgate.neted.ac.ukkoreamed.orgfrontiersin.org

A key consequence of this compound's action on the myenteric plexus is the inhibition of neurotransmitter release. Specifically, this compound significantly reduces the release of acetylcholine and prostaglandins within the gastrointestinal tract. drugbank.compatsnap.comresearchgate.netresearchgate.netdrugs.comhres.cadroracle.aihres.ca By diminishing the availability of these excitatory neurotransmitters, this compound effectively reduces propulsive peristalsis and consequently increases intestinal transit time. drugbank.comdrugs.comhres.cadroracle.aihres.ca Studies have shown that the inhibited acetylcholine release can be reversed by naloxone, suggesting an interaction with opiate receptor sites in the myenteric plexus. researchgate.net The inhibition of prostaglandin release may also involve the prevention of prostaglandin biosynthesis from arachidonic acid in the intestine. researchgate.net

Despite being a potent opioid receptor agonist, this compound exhibits remarkable peripheral selectivity, meaning its primary therapeutic effects are confined to the gastrointestinal tract with limited penetration into the central nervous system (CNS) at recommended therapeutic doses. drugbank.comwikipedia.orgpatsnap.comed.ac.ukkoreamed.orgresearchgate.netnih.govwikipedia.orgnih.govpharmacytimes.comnih.gov This peripheral restriction is a critical pharmacological feature that minimizes the typical CNS-related side effects associated with other opioid analgesics, such as euphoria or respiratory depression. drugbank.compatsnap.comed.ac.ukwikipedia.orgnih.govpharmacytimes.com This limited CNS penetration is attributed to several factors, including its low oral bioavailability and extensive first-pass metabolism. drugbank.comwikipedia.orgdrugs.comhres.canih.govnih.govpharmacytimes.com

A significant contributor to this compound's peripheral selectivity is its interaction with the P-glycoprotein (P-gp) efflux pump. drugbank.comwikipedia.orgresearchgate.netnih.govwikipedia.orgpharmacytimes.comsnmjournals.orgnih.govresearchgate.net P-gp is an ATP-binding cassette-dependent efflux transporter widely expressed in various tissues, including the endothelial cells of the blood-brain barrier. researchgate.netwikipedia.orgsnmjournals.orgresearchgate.net this compound is an avid substrate for P-gp, meaning the pump actively transports this compound out of the CNS, effectively preventing its accumulation in the brain. drugbank.comwikipedia.orgresearchgate.netwikipedia.orgpharmacytimes.comsnmjournals.orgnih.govresearchgate.net This active efflux mechanism is instrumental in limiting this compound's CNS exposure and contributes to its favorable safety profile at therapeutic concentrations. drugbank.comresearchgate.netwikipedia.orgpharmacytimes.comsnmjournals.orgnih.gov

Effects on Colonic Motility

Absorption and Bioavailability

Loperamide is well absorbed from the gastrointestinal tract following oral administration. drugbank.com However, despite good absorption, its systemic bioavailability is remarkably low due to significant first-pass metabolism. drugbank.comnih.govmedsafe.govt.nzhres.camedicines.org.ukvettimes.com

Distribution and Protein Binding

This compound exhibits a large volume of distribution and high plasma protein binding. drugbank.comnih.govfda.gov Approximately 95% to 97% of this compound in the blood is bound to plasma proteins, primarily albumin. drugbank.commedsafe.govt.nzhres.camedicines.org.ukvettimes.comfda.govwikipedia.org Despite its lipophilic nature, this compound generally acts peripherally and does not readily cross the blood-brain barrier at therapeutic doses. drugbank.comresearchgate.netwikipedia.orgnih.gov This is largely attributed to its being a substrate for P-glycoprotein (P-gp), an efflux transporter located in the intestinal wall and at the blood-brain barrier, which actively pumps the drug out of cells and limits its systemic and CNS penetration. drugbank.commedsafe.govt.nzhres.camedicines.org.ukvettimes.comwikipedia.orgnih.govfrontiersin.orgdrugs.com

Biotransformation

This compound undergoes extensive biotransformation, with almost complete extraction by the liver where it is predominantly metabolized, conjugated, and subsequently excreted via the bile. medsafe.govt.nzhres.camedicines.org.uk The main metabolic pathway for this compound is oxidative N-demethylation. drugbank.commedsafe.govt.nzhres.camedicines.org.ukfda.govdrugs.com This process leads to the formation of metabolites such as N-demethyl this compound (also known as desmethyl-loperamide), which are generally considered pharmacologically inactive. drugbank.commedsafe.govt.nz

Elimination and Excretion

The elimination of this compound and its metabolites from the body is a well-characterized process. citeab.comnih.govuni.luwikipedia.orgguidetopharmacology.orgfishersci.canih.govfishersci.caresearchgate.netfishersci.ca

Electrophysiological Alterations

Associated Arrhythmias and Cardiac Events

High concentrations of this compound can lead to a combination of conduction slowing and alterations in repolarization time, resulting in cardiac proarrhythmia and life-threatening ventricular arrhythmias. wikipedia.orguni.luguidetopharmacology.orgfishersci.ca These include, but are not limited to, Torsades de Pointes (TdP), ventricular tachycardia, ventricular fibrillation, atrioventricular block, Brugada syndrome ECG features, cardiac arrest, and sudden death. wikipedia.orgfishersci.cauni.luguidetopharmacology.org The exact mechanisms are complex but are primarily linked to this compound's inhibitory effects on cardiac ion channels. wikipedia.orguni.lu

Acute Diarrhea Management

Loperamide is a primary treatment option for acute, non-specific diarrhea, including traveler's diarrhea. medcentral.comaafp.org Its effectiveness in this context is well-documented through clinical studies.

Chronic Diarrhea Management

This compound is also effective in controlling and providing symptomatic relief for chronic diarrhea, including that associated with inflammatory bowel disease and post-gastrointestinal surgery. medcentral.comnih.gov

Chemotherapy-Induced Diarrhea (CID)

Chemotherapy-induced diarrhea (CID) represents a significant and often dose-limiting toxicity in cancer treatment. This compound is widely recognized as a primary first-line therapy for the management of CID biotech-asia.orgjhoponline.comeviq.org.au. It is specifically recommended for managing Grade 2 CID, characterized by more severe diarrhea that may necessitate medical intervention biotech-asia.org. The mechanism involves its agonistic effects on opioid receptors in the gastrointestinal (GI) tract, leading to decreased peristalsis and increased fluid reabsorption jhoponline.com. While generally effective, standard or high-dose this compound therapy may not be successful in all cases, with 9% to 30% of aggressive CID cases proving refractory jhoponline.com. In instances where diarrhea persists beyond 24 to 48 hours despite high-dose this compound, alternative treatments such as subcutaneous octreotide or oral budesonide may be considered jhoponline.comengland.nhs.uk. It is crucial to note that antidiarrheal agents like this compound are contraindicated if immune-related colitis is suspected eviq.org.au.

Fecal Incontinence Management

This compound is a preferred pharmacological agent for the management of fecal incontinence, particularly when the condition is associated with liquid stool gastroenterologyandhepatology.netmedscape.comjst.go.jp. Its mechanism of action in this context involves increasing gut transit time, which facilitates increased water absorption from the stool, leading to a firmer, more manageable consistency medscape.com. Additionally, this compound may enhance the tone of the internal anal sphincter (IAS), further contributing to improved continence gastroenterologyandhepatology.netmedscape.comjst.go.jp. Research has explored this compound's efficacy in managing fecal incontinence, sometimes in conjunction with other conservative therapies such as fiber supplements or biofeedback gastroenterologyandhepatology.netucc-today.comdiva-portal.orgresearchgate.netpelvicfloordisordersnetwork.org. A prospective controlled study involving women with fecal incontinence found that treatment with methylcellulose and this compound resulted in a significantly higher cure rate (46%) compared to expectant management (0%) (p<0.01) researchgate.net. While effective, some reviews indicate that the evidence base for this compound's use in fecal incontinence can be limited, and potential side effects should be considered ucc-today.com.

Combination Therapies (e.g., with Simethicone)

This compound is frequently combined with simethicone to provide symptomatic relief for acute diarrhea that is accompanied by gas-related abdominal discomfort, including bloating, cramping, and flatulence bmj.comimodium.comalberta.cagoodrx.commedex.com.bdclinicaltrials.eunih.gov. In this combination, this compound works to slow down intestinal movement and reduce the water content of stool, while simethicone functions as an anti-foaming agent, aiding in the breakdown and passage of gas bubbles in the gut alberta.cagoodrx.commedex.com.bd. Randomized controlled trials have demonstrated that the co-administration of this compound and simethicone is clinically more effective than either drug administered alone in alleviating the duration and symptoms of acute diarrhea, including a faster resolution of gas-related symptoms bmj.comacpjournals.orgresearchreview.co.nz. One study reported that the combination product achieved a significantly higher patient-assessed rating at the end of the study compared to individual components or placebo (p<0.001) researchreview.co.nz. A completed Phase 3 trial further investigated the efficacy and safety of a this compound hydrochloride/simethicone chewable tablet formulation for the treatment of acute diarrhea with associated abdominal discomfort and flatulence drugbank.comfda.gov.

Historical Reassessment of Abuse Potential

Initially synthesized in 1969 and medically used since 1976, loperamide was once categorized as a Schedule V drug by the Federal Drug Administration (FDA) due to its opioid-like misuse potential, before becoming available without a prescription in 1988 nih.gov. For a long time, it was believed to have low abuse potential pedemmorsels.comresearchgate.netpowerpak.comwikipedia.org. However, over the past decade, there has been a concerning rise in documented cases of this compound misuse and abuse addictioncenter.compedemmorsels.compowerpak.comwikipedia.org.

Epidemiological trends from the National Poison Data System (NPDS) revealed a 71% increase in calls related to intentional this compound exposure between 2011 and 2014 upstate.edupowerpak.com. Similarly, web-forum postings discussing oral this compound abuse increased tenfold between 2010 and 2011 addictioncenter.comupstate.edunih.gov. This surge in abuse aligns with the broader opioid epidemic, as individuals seek alternative, more accessible, and cheaper substances to manage opioid withdrawal or achieve euphoric effects addictioncenter.comupstate.edu. The FDA issued a Drug Safety Communication in June 2016, highlighting serious and fatal cardiac events associated with high-dose this compound use, and later, in January 2018, approved new packaging with fewer doses to deter abuse powerpak.comfda.gov.

Motivations for Supratherapeutic Use

Individuals engage in supratherapeutic use of this compound primarily for two reasons: to self-treat opioid withdrawal symptoms and to induce euphoria and analgesia drugbank.comaddictioncenter.comnih.govpedemmorsels.comupstate.edupowerpak.comfda.govnjpies.org.

Pharmacokinetic Manipulation to Enhance Central Effects

To enhance this compound's central effects and overcome its limited blood-brain barrier penetration, users often co-administer it with other substances that alter its pharmacokinetics frontiersin.orgmedicaltoxic.compowerpak.comfda.govdrugs.commedcentral.com. This compound is a substrate for both P-glycoprotein (P-gp) and the cytochrome P450 (CYP) enzymes, specifically CYP3A4 and CYP2C8 drugbank.comnih.govfrontiersin.orgwikipedia.orgmedcentral.comtg.org.aunih.govresearchgate.netmedsafe.govt.nzresearchgate.net.

Tolerance and Dependence Mechanisms

At therapeutic doses, this compound functions as an opioid receptor agonist, primarily targeting μ-opioid receptors within the myenteric plexus of the large intestine to reduce gastrointestinal motility. wikipedia.orgmims.comed.ac.uk Its limited central nervous system (CNS) effects at these doses are attributed to its poor oral bioavailability, extensive first-pass metabolism, and active efflux by the P-glycoprotein (P-gp) transporter, which effectively pumps the drug out of the brain. wikipedia.orged.ac.ukpowerpak.comnih.gov

However, when this compound is consumed in significantly higher, supratherapeutic doses (often exceeding 70 mg), it can saturate the P-gp transporter. wikipedia.orgnih.govresearchgate.netnih.gov This saturation allows this compound to bypass the efflux mechanism and penetrate the CNS, where it can then exert central opioid-like effects, including euphoria. wikipedia.orgnih.govresearchgate.netnih.gov Prolonged use at these elevated doses can lead to the development of both tolerance and physical dependence. wikipedia.orgresearchgate.net

Studies in animals have demonstrated that parenteral administration of this compound can induce physical dependence and cross-tolerance to other opioids. drugs.com For instance, in morphine-dependent monkeys, high doses of this compound were shown to prevent the manifestation of morphine withdrawal signs. drugs.commedcentral.com While tolerance to the antidiarrheal effect of this compound has generally not been reported in humans, the drug's opioid agonist activity, particularly when it achieves CNS penetration at high doses, underlies the potential for physical dependence. ed.ac.ukdrugs.commedcentral.com

Withdrawal Symptoms Upon Abrupt Cessation

Abrupt discontinuation of chronic, high-dose this compound use can precipitate a range of withdrawal symptoms that are characteristic of opioid withdrawal syndrome. wikipedia.orgresearchgate.netaddictioncenter.comswissmedic.chnih.gov These symptoms arise from the body's physiological adaptation to the continuous presence of the opioid agonist and the subsequent disruption upon its removal.

Commonly reported withdrawal symptoms include:

Nausea and vomiting addictioncenter.com

Anxiety and irritability addictioncenter.comswissmedic.ch

Depression addictioncenter.com

Abdominal cramps and diarrhea (rebound effect) addictioncenter.comswissmedic.chunitedrecoveryproject.com

Excessive sweating addictioncenter.com

Muscle aches and pains addictioncenter.com

Restlessness swissmedic.chunitedrecoveryproject.com

Intestinal colic swissmedic.ch

While the severity of this compound withdrawal symptoms may vary, they can cause significant discomfort and distress, often compelling individuals to continue using the drug to alleviate these unpleasant sensations. unitedrecoveryproject.com

Epidemiology and Trends of this compound Misuse

This compound misuse has emerged as a growing public health concern, particularly in the United States. nih.govnih.govmedicaltoxic.comnih.govresearchgate.net It has been colloquially termed "the poor man's methadone" due to its increasing use as an accessible and inexpensive alternative for managing opioid withdrawal symptoms or, less frequently, for achieving euphoric effects. wikipedia.orgnih.govresearchgate.netnih.gov

Data from the National Poison Data System (NPDS) in the United States reveal a significant escalation in intentional this compound exposures. Between 2010 and 2015, there was a 91% increase in reported cases. powerpak.comnih.govmedicaltoxic.comnih.govmdpi.comresearchgate.net This trend indicated an approximate increase of 38 new cases annually during that period. nih.govmedicaltoxic.com

The demographic analysis of this compound misuse indicates that a substantial proportion of cases, roughly one-third, involve teenagers and young adults. powerpak.commedicaltoxic.comnih.govmdpi.com Furthermore, male individuals are more frequently implicated in intentional this compound abuse, accounting for 77% of 179 cases reported to the NPDS between 2008 and 2016, with a median age of 26 years. powerpak.comnih.govmedicaltoxic.commdpi.com Conversely, female subjects were more often involved in reported suicidal attempts using this compound. powerpak.commdpi.com A critical risk factor identified in these trends is a history of previous substance use, particularly opioid abuse; in a review of New York cases, 68% of individuals reported prior opioid abuse. medicaltoxic.com

The rise in this compound misuse has also been mirrored by increased online interest. Google Trends analyses show a pronounced increase in searches for terms such as "this compound high" and "this compound withdrawal" starting around 2010-2011, reflecting growing public awareness and discussion of its illicit uses. powerpak.comnih.gov The widespread availability and low cost of this compound are significant contributing factors to its appeal for misuse. nih.govnih.govmdpi.com

However, regulatory interventions have shown a positive impact. Following warnings issued by the U.S. Food and Drug Administration (FDA) in 2016 regarding the risks associated with high-dose this compound use, coupled with labeling requirements and packaging restrictions, a trend reversal has been observed. researchgate.netresearchgate.net Reports of intentional misuse, abuse, and suspected suicide related to this compound to US poison centers have shown a decrease after 2017, suggesting the potential effectiveness of such public health measures. researchgate.net

Table: Trends in Intentional this compound Exposures (US National Poison Data System, 2010-2015) powerpak.comnih.gov

Table: Reasons for Intentional this compound Exposure (US National Poison Data System, 2010-2015) powerpak.com

Animal Models for Gastrointestinal Motility Studies

Loperamide is frequently employed in animal models to induce a state of reduced gastrointestinal motility, mimicking conditions such as constipation. These models are valuable for studying the underlying mechanisms of GI dysmotility and for evaluating potential therapeutic interventions.

This compound is a commonly utilized agent to induce constipation in various animal species, including rats and mice. This induction allows researchers to investigate the pathophysiology of constipation and to assess the efficacy of novel laxative agents or prokinetic compounds scielo.brmdpi.comresearchgate.netfrontiersin.orgnih.govmdpi.comscielo.br. Administration of this compound leads to a notable reduction in defecation frequency, decreased fecal water content, and diminished fecal quantity mdpi.comfrontiersin.orgmdpi.comfrontiersin.orgscielo.br. Furthermore, it significantly prolongs intestinal transit time, a key indicator of constipation mdpi.comresearchgate.netmdpi.comscielo.brfrontiersin.orgscielo.brresearchgate.netnih.govcambridge.orgjmb.or.kr.

Doses of this compound used to induce constipation vary depending on the animal model and study design. In mice and rats, doses such as 5 mg/kg have been administered nih.govmdpi.comfrontiersin.orgresearchgate.netnih.gov. Higher doses, including 7.5 mg/kg and 10 mg/kg, have also been employed in mice nih.gov. The duration of this compound administration typically ranges from 7 to 14 days mdpi.comresearchgate.netmdpi.comfrontiersin.orgnih.gov. Parameters commonly assessed in these models include fecal weight, fecal water content, defecation frequency, intestinal length, and intestinal transit rate or time mdpi.comfrontiersin.orgmdpi.comscielo.brfrontiersin.orgscielo.brresearchgate.netnih.govjmb.or.kr.

Table 1: Effects of this compound in Animal Models of Constipation

Assessment of gastrointestinal transit rate in animal models often involves methods such as the charcoal meal transit test. In this technique, a non-absorbable marker like charcoal is orally administered, and the distance it travels through the intestines within a specific timeframe is measured jmb.or.kr. This compound administration consistently leads to a significant reduction in the intestinal transit rate mdpi.comfrontiersin.orgmdpi.comscielo.brjmb.or.kr. For example, in one study, the intestinal transit rate was notably reduced to approximately 38% in the this compound-treated group compared to 81% in the normal control group of mice jmb.or.kr. Another metric, the Oroanal Transit Time (OATT), also demonstrates a substantial increase in this compound-treated animals, with one study reporting a 90.5% increase in the this compound group, resulting in an OATT of 16.0 ± 1.9 hours compared to 8.4 ± 1.4 hours in controls scielo.br.

Interstitial Cells of Cajal (ICC) are specialized pacemaker cells crucial for regulating gastrointestinal motility. Research indicates that this compound administration is associated with a reduction in the number or expression levels of ICC biomarkers, such as c-kit and anoctamin-1 (ANO1) scielo.brfrontiersin.orgscielo.brnih.govkosfaj.orgresearchgate.net. Furthermore, in vitro studies have shown that this compound can induce apoptosis of ICC in a time- and concentration-dependent manner, with an observed IC50 of approximately 12 µM at 48 hours researchgate.net. This observed decrease in ICC is directly linked to the impaired colonic motility characteristic of this compound-induced constipation models scielo.brscielo.br.

In Vitro Ion Channel Studies for Cardiotoxicity

In vitro studies using isolated cells or expression systems are vital for understanding the direct effects of this compound on cardiac ion channels, which can be relevant to its pharmacological profile.

This compound has been identified as a potent inhibitor of the human ether-à-go-go-related gene (hERG) potassium channel, which carries the rapidly activating delayed rectifier potassium current (IKr) in cardiac myocytes. Inhibition of hERG can prolong cardiac repolarization. Studies have reported varying inhibitory concentrations (IC50) for this compound on hERG channels. In Chinese hamster ovary (CHO) cells, the IC50 for hERG channel blockade was approximately 40 nmol/L (40 nM) for inhibition of tail currents jacc.org. Other studies using HEK293 cells have reported IC50 values of 0.390 µM (390 nM) semanticscholar.orgnih.govmdpi.comnih.gov. Additional reported values for hERG inhibition range from 33 nM to 88 nM semanticscholar.orgnih.gov, and between 15.7–20.5 µg/L, which corresponds to approximately 33-43 nM based on this compound's molar mass tandfonline.com.

Table 2: this compound's hERG (IKr) Current Inhibition (In Vitro)

This compound has also been shown to inhibit various voltage-gated sodium channels (INa) in in vitro models. Inhibition of sodium channels can affect cardiac conduction. Studies indicate that this compound inhibits Nav1.5-mediated sodium current with an IC50 of 0.526 µM (526 nM) semanticscholar.orgnih.govmdpi.comnih.gov. Furthermore, this compound has demonstrated inhibitory effects on other sodium channel subtypes. For Nav1.7 channels, an IC50 of 1.86 ± 0.11 µM was reported for the resting state in HEK293 cells researchgate.netnih.gov. On recombinant Nav1.8 channels in ND7/23 cells, the IC50 was 0.60 ± 0.10 µM, with a higher potency observed on native Nav1.8 channels in dorsal root ganglion (DRG) neurons (0.11 ± 0.08 µM) researchgate.netnih.gov. Weaker potency was noted for Nav1.9 channels, with an IC50 of 3.48 ± 0.33 µM researchgate.netnih.gov. Other reported values for INa inhibition include 2900 nM using a high-throughput screening system in CHO cells and 239 nM via manual patch clamp in HEK293 cells semanticscholar.orgnih.gov.

Table 3: this compound's Sodium Channel (INa) Current Inhibition (In Vitro)

In Silico Cardiac Electrophysiological Modeling

In silico cardiac electrophysiological modeling has been instrumental in understanding the potential cardiac effects of this compound, particularly at concentrations exceeding therapeutic levels. Studies employing human ventricular action potential models have confirmed that this compound exhibits a substantial safety margin at therapeutic exposures, typically up to 600 times its human Free Therapeutic Plasma Concentration (FTPC). mims.commims.comthermofisher.com

However, at extreme overdose concentrations, these in silico trials predict significant alterations in cardiac electrophysiology, including repolarization abnormalities and conduction slowing, which can lead to cardiac proarrhythmias. mims.commims.comthermofisher.com The primary mechanisms underlying this cardiac electrophysiological toxicity at overdose exposures are identified as the inhibition of the human Ether-à-go-go-Related Gene (hERG)-mediated IKr current and the sodium current (INa). mims.commims.comthermofisher.com this compound has been shown to inhibit hERG (IKr), INa, and ICa currents with specific half-maximal inhibitory concentration (IC50) values. mims.commims.comthermofisher.com These IC50 values are considerably higher than the FTPC, reinforcing the safety margin at standard therapeutic doses. mims.commims.comthermofisher.com

The observed effects on ion channels are summarized in the table below:

Further in silico investigations have explored the potential for co-medications to influence this compound's cardiac effects. For instance, the combination of this compound with hydroxyzine in simulated action potential models appeared to mitigate abnormal action potential intervals compared to this compound administered alone. fishersci.ca

Preclinical Studies on Central Opioid Action

This compound is characterized as a piperidine derivative opioid ligand that primarily activates peripheral opioid receptors, with minimal penetration into the central nervous system (CNS) at therapeutic doses. wikipedia.orguni.lu This peripheral selectivity is largely attributed to its low oral absorption and its efficient efflux from the CNS by P-glycoprotein. wikipedia.orguni.lu

Despite its peripheral action at normal doses, preclinical studies have investigated the potential for central opioid effects under specific conditions. High doses of this compound administered to mice, rats, and rhesus monkeys have been shown to induce a mild physical dependence, with observable mild opiate withdrawal symptoms upon abrupt cessation of long-term treatment. wikipedia.orgresearchgate.net

The co-administration of this compound with P-glycoprotein inhibitors, such as quinidine, has been demonstrated to facilitate its passage across the blood-brain barrier, resulting in central morphine-like effects, including respiratory depression. researchgate.net Moreover, at extremely high doses (exceeding 70 mg), this compound can saturate P-glycoprotein, thereby overcoming the efflux mechanism and potentially leading to psychoactive effects. researchgate.net

While animal studies generally indicate that this compound lacks significant analgesic properties at typical therapeutic doses (2 to 16 mg/kg), some research in animal models of pain has reported antinociceptive effects following systemic or intraspinal administration. wikipedia.orgnih.govnih.gov For example, topical application of this compound at the site of inflammation in a thermal injury-induced hyperalgesia rat model produced a dose-dependent antihyperalgesic effect, which was reversible by naloxone, confirming a peripheral opioid-mediated action. nih.gov

Studies on Novel this compound Analogs and Opioid Receptor Agonists

This compound functions as a µ-opioid receptor (MOR) agonist, exhibiting notable affinity and selectivity for the cloned human µ-opioid receptor over the δ-opioid receptor. fishersci.sewikipedia.orgnih.gov Automated docking studies have suggested that this µ/δ selectivity may stem from the differential accommodation of this compound's two phenyl groups within distinct lipophilic pockets of the µ- and δ-opioid receptors. wikipedia.org

The structural characteristics of this compound, particularly its 4-phenylpiperidine scaffold, have served as a basis for the design and synthesis of novel analogs aimed at developing new µ-opioid receptor agonists. wikipedia.orgnih.govnih.gov Researchers have synthesized compounds based on the chemical structures of this compound and diphenoxylate, with the intent of creating potent MOR agonists. nih.gov

Key examples of these novel this compound analogs include:

Compound 5: This analog incorporates two 4-phenylpiperidine scaffolds, and its synthesis has been optimized to achieve excellent yields. wikipedia.orgnih.govnih.gov

Compounds 6 and 7: Each of these analogs features a single 4-phenylpiperidine scaffold. wikipedia.orgnih.govnih.gov

These synthesized analogs are considered promising candidates for future development as MOR agonists. nih.gov Beyond direct structural analogs, research has also explored compounds with mixed opioid receptor activity. For instance, FBNTI, a novel compound, has been identified as a potent delta opioid receptor (DOR) antagonist that also acts as a MOR agonist through an allosteric mechanism, demonstrating a significantly higher affinity for DOR compared to MOR. wikipedia.org Another compound, MuDelta, designed as a mixed µ opioid receptor agonist and δ opioid receptor antagonist, has been investigated for its ability to normalize gastrointestinal motility without inducing constipation. Preclinical studies with MuDelta showed very low plasma levels after oral administration and demonstrated its capacity to normalize gastrointestinal transit in stressed mice over a broader dose range than this compound. nih.gov