Derivative Of Naltrexone Research Articles

In Silico Interactions of Morphine Opioids with TLR4 and TRPV1 Targets

By the importance of exploring new inhibitors or antagonists for the over-activity of each of Toll-Like Receptor 4 (TLR4) and Transient Receptor Potential Vanilloid 1 (TRPV1) targets, derivatives of morphine opioid were investigated in this work using the in silico methodology. The original morphine and three derivatives of oxymorphone, naloxone, and naltrexone were considered the parent ligands (L1-L4), and the C-3-O-Alky functionalized models were considered as functionalized ligands (L5-L8). The singular models of ligands were optimized to obtain the minimized energy structures, and molecular docking simulations were performed to examine their interactions with the targets. The optimizations indicated significant variations of the frontier electronic molecular orbital levels proposing different activities for the ligands. Next, molecular docking simulations showed that L1 (the original morphine) was at the lowest suitability of complex formation and L8 was at the highest suitability of complex formation with both TLR4 and TRPV1 targets. Consequently, optimizing the morphine lead compound for obtaining more suitable ligands was achieved for proposing new inhibitors or antagonists for the investigated TLR4 and TRPV1 targets.

Nalmefene and alcohol dependence: A new approach or the same old unacceptable marketing?

Nalmefene and alcohol dependence: A new approach or the same old unacceptable marketing?

Design, synthesis, and biological evaluation of 14-heteroaromatic-substituted naltrexone derivatives: pharmacological profile switch from mu opioid receptor selectivity to mu/kappa opioid receptor dual selectivity.

On the basis of a mu opioid receptor (MOR) homology model and the isosterism concept, three generations of 14-heteroaromatically substituted naltrexone derivatives were designed, synthesized, and evaluated as potential MOR-selective ligands. The first-generation ligands appeared to be MOR-selective, whereas the second and the third generation ones showed MOR/kappa opioid receptor (KOR) dual selectivity. Docking of ligands 2 (MOR selective) and 10 (MOR/KOR dual selective) to the three opioid receptor crystal structures revealed a nonconserved-residue-facilitated hydrogen-bonding network that could be responsible for their distinctive selectivity profiles. The MOR/KOR dual-selective ligand 10 showed no agonism and acted as a potent antagonist in the tail-flick assay. It also produced less severe opioid withdrawal symptoms than naloxone in morphine-dependent mice. In conclusion, ligand 10 may serve as a novel lead compound to develop MOR/KOR dual-selective ligands, which might possess unique therapeutic value for opioid addiction treatment.

Opioid receptor selectivity profile change via isosterism for 14-O-substituted naltrexone derivatives

Isosterism is commonly used in drug discovery and development to address stability, selectivity, toxicity, pharmacokinetics, and efficacy issues. A series of 14-O-substituted naltrexone derivatives were identified as potent mu opioid receptor (MOR) antagonists with improved selectivity over the kappa opioid receptor (KOR) and the delta opioid receptor (DOR), compared to naltrexone. Since esters are not metabolically very stable under typical physiological conditions, their corresponding amide analogs were thus synthesized and biologically evaluated. Unlike their isosteres, most of these novel ligands seem to be dually selective for the MOR and the KOR over the DOR. The restricted flexibility of the amide bond linkage might be responsible for their altered selectivity profile. However, the majority of the 14-N-substituted naltrexone derivatives produced marginal or no MOR stimulation in the 35S-GTP[γS] assay, which resembled their ester analogs. The current study thus indicated that the 14-substituted naltrexone isosteres are not bioisosteres since they have distinctive pharmacological profile with the regard to their opioid receptor binding affinity and selectivity.

Preclinical Disposition (In Vitro) of Novel μ-Opioid Receptor Selective Antagonists

Recently, two novel N-heterocyclic derivatives of naltrexone [designated 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)acetamido]morphinan (NAP) and 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[(3'-isoquinolyl) acetamido]morphinan (NAQ)] have been proposed as μ-opioid receptor (MOR) selective antagonists. The goal of this study was to examine their absorption and metabolism. The bidirectional transport of NAP and NAQ was determined in Caco-2 and MDCKII-MDR1 cells, and the permeability directional ratio (PDR) was estimated (PDR = P(app, B-A)/P(app, A-B), where P(app) is the apparent permeability, A is apical, and B is basolateral). Oxidative metabolism of NAQ (0.5-80 μM) and NAP (0.5-30 μM) was determined in pooled human liver microsomes. The reaction monitored the disappearance of NAQ/NAP. NAP and NAQ were quantitated by high-performance liquid chromatography-UV at 270 or 232 nm, respectively. The permeability of NAQ or NAP was similar to that of naltrexone or paracellular markers, respectively. NAP also exhibited a high PDR and was determined to be a P-glycoprotein (P-gp) substrate. Unbound fractions in human plasma for NAQ and NAP were 0.026 ± 0.019 and 0.85 ± 0.12, respectively. The metabolic oxidative reaction rates, fitted to a Michaelis-Menten model, yielded K(m) and V(max) values of 15.8 ± 5.5 μM and 192 ± 24 pmol/min for NAQ and 1.8 ± 1.5 μM and 8.1 ± 1.4 pmol/min for NAP. Intrinsic hepatic clearance was estimated to be 13 and 5 ml · min(-1) · kg(-1) for NAQ and NAP, respectively. Neither NAQ nor NAP underwent detectable glucuronidation. Thus, NAP was a P-gp substrate with low apparent permeability, whereas NAQ was not a P-gp substrate and showed better permeability. Therefore, in contrast to NAP, NAQ would be more suitable for oral absorption and penetration of the blood-brain barrier, yielding potential pharmacokinetic and pharmacodynamic advantages over naltrexone.

Opioid-like compound exerts anti-fibrotic activity via decreased hepatic stellate cell activation and inflammation

Hepatic fibrosis is characterized by excess type I collagen deposition and exacerbated inflammatory response. Naltrexone, an opioid receptor antagonist used for treating alcohol abuse, attenuates hepatocellular injury in fibrotic animal models, which can be accompanied by deleterious side effects. Additionally, opioid neurotransmission is upregulated in patients with inflammatory liver disease. Several derivatives of Naltrexone, Nalmefene (Nal) and JKB-119, exert immunomodulatory activity; however, unlike Nal, JKB-119 does not show significant opioid receptor antagonism. To delineate the potential hepatoprotective effects of these compounds, we investigated if JKB-119 and Nal could modulate activation of hepatic stellate cells (HSCs), primary effector cells that secrete type I collagen and inflammatory mediators during liver injury. Our results demonstrated that Nal or JKB-119 treatment decreased smooth muscle α-actin, a marker of HSC activation, mRNA and protein expression. Despite decreased collagen mRNA expression, both compounds increased intracellular collagen protein expression; however, inhibition of collagen secretion was observed. To address a possible mechanism for suppressed collagen secretion or retention of intracellular collagen, endoplasmic (ER) protein expression and matrix metalloproteinase (MMP) activity were examined. While no change in ER protein expression (Grp78, PDI, Hsp47) was observed, MMP13 mRNA expression was dramatically increased. In an acute LPS inflammatory injury animal model, JKB-119 treatment decreased liver injury (ALT), plasma TNFα and PMN liver infiltration. Overall, these results suggest that JKB-119 can directly inhibit HSC activation attributed to anti-inflammatory activity and may, therefore, attenuate inflammation associated with HSC activation and liver disease.

Investigation of Beckett–Casy model 3: Synthesis of novel naltrexone derivatives with contracted and expanded D-rings and their pharmacology

Novel naltrexone derivatives 7 and 8 with contracted and expanded D-rings were synthesized to investigate the importance of orientation of lone electron pair on the nitrogen for binding abilities to the opioid receptor. Compound 7 showed almost no binding affinity, whereas compound 8 was comparable to naltrexone (6) in binding affinity. Conformational analyses and NOE experiments in D2O of compounds 6–8 suggested that the lone electron pairs of compounds 6 and 8 with respective six- and seven-membered D-rings would project in the pseudo-axial orientation, whereas compound 7 with five-membered D-ring would have the lone electron pair directing in pseudo-equatorial position. These results strongly supported the proposal that the axial orientation of the lone electron pair on nitrogen would provide sufficient binding abilities to the opioid receptor and that the 15–16 ethylene moiety in the morphine structure would play a role in fixation of the lone electron pair in the axial direction rather than interaction with the putative cavity in the Beckett–Casy model.

A Review of the Treatment of Opioid-induced Constipation with Methylnaltrexone Bromide

Objectives Review and summarize the mechanism of action of methylnaltrexone bromide (methylnaltrexone) and its effectiveness in the treatment of opioid-induced constipation. Data Source A multi-database search was conducted using PubMed and MEDLINE databases, in addition to electronic links to related articles and references. Background Opioids are effective medications for the management of moderate to severe pain, but they are associated with a number of side effects, especially within the gastrointestinal system. Constipation is a very common adverse reaction in patients with late-stage, adverse illness, who require long term administration of opioids on a chronic basis to help alleviate pain. In April 2008, the Food and Drug Administration approved the use of methylnaltrexone, a quaternary derivative of naltrexone which does not cross the blood brain barrier, for the management of patients with opioid-induced constipation. Methylnaltrexone acts as a selective peripheral Mu-receptor antagonist, without affecting the effects of opioids on central analgesia. Conclusions Studies have been shown that methylnaltrexone can be used safely in the treatment of opioid-induced constipation without either interfering with opioid effects on central anesthesia or precipitating opioid withdrawal.

Methylnaltrexone: a novel approach for the management of opioid-induced constipation in patients with advanced illness

In April 2008, the US FDA granted approval to methylnaltrexone (Relistor®), the first peripheral µ-opioid-receptor antagonist for the treatment of opioid-induced constipation in advanced-illness patients receiving palliative care and for whom other laxative therapies failed to achieve adequate results. Methylnaltrexone, a quaternary derivative of naltrexone, introduces a novel mechanism of action that selectively antagonizes the peripheral µ-receptors in the GI tract without effects on the CNS. In clinical trials, subcutaneous methylnaltrexone reversed opioid-induced constipation after the first dose in approximately 50–60% of the patients. In most of the cases, effective laxation occurred within 1 h. The therapeutic benefit was sustained in multiple-dose studies. Owing to the nature of the population studied, safety data are available for approximately 4 months of use. Although it is not the focus of this article, methylnaltrexone’s mechanism of action suggests it could be beneficial for other peripheral, opioid-induced adverse effects, such as opioid-related nausea, vomiting, urinary retention, pruritus or postoperative ileus.

A Simple and Sensitive Analytical Method for Determination of Naltrexone Level in Plasma by GC–MS

A gas chromatography-mass spectrometry method for determination of naltrexone in plasma is presented. The method is based on pre-column derivatization of analyte to trimethylsilyl derivative of naltrexone. The analyte and internal standard were extracted from plasma by liquid–liquid extraction. Validation of the method has been studied in the concentration range 1–50 ng mL−1.

14- O-Heterocyclic-substituted naltrexone derivatives as non-peptide mu opioid receptor selective antagonists: Design, synthesis, and biological studies

Mu opioid receptor antagonists have clinical utility and are important research tools. To develop non-peptide and highly selective mu opioid receptor antagonist, a series of 14- O-heterocyclic-substituted naltrexone derivatives were designed, synthesized, and evaluated. These compounds showed subnanomolar-to-nanomolar binding affinity for the mu opioid receptor. Among them, compound 1 exhibited the highest selectivity for the mu opioid receptor over the delta and kappa receptors. These results implicated an alternative ‘address’ domain in the extracellular loops of the mu opioid receptor.

Methylnaltrexone in the treatment of opioid-induced constipation.

Constipation is a significant problem related to opioid medications used to manage pain. This review attempts to outline the latest findings related to the therapeutic usefulness of a μ opioid receptor antagonist, methylnaltrexone in the treatment of opioid-induced constipation. The review highlights methylnaltrexone bromide (Relistor™; Progenics/Wyeth) a quaternary derivative of naltrexone, which was recently approved in the United States, Europe and Canada. The Food and Drug Administration in the United States approved a subcutaneous injection for the treatment of opioid bowel dysfunction in patients with advanced illness who are receiving palliative care and when laxative therapy has been insufficient. Methylnaltrexone is a peripherally restricted, μ opioid receptor antagonist that accelerates oral-cecal transit in patients with opioid-induced constipation without reversing the analgesic effects of morphine or inducing symptoms of opioid withdrawal. An analysis of the mechanism of action and the potential benefits of using methylnaltrexone is based on data from published basic research and recent clinical studies.

A Novel Delta Opioid Receptor Antagonist, SoRI-9409, Produces a Selective and Long-Lasting Decrease in Ethanol Consumption in Heavy-Drinking Rats

Naltrexone, a compound with high affinity for the mu opioid receptor (MOP-R) reduces alcohol consumption. SoRI-9409 is a derivative of naltrexone that has highest affinity at delta opioid receptors (DOP-Rs). We have investigated the effects of SoRI-9409 on ethanol consumption to determine the consequences of altering the naltrexone compound to a form with increased efficacy at DOP-Rs. Effects of the opioid receptor antagonists, SoRI-9409 (0-30 mg/kg, IP), naltrexone (0-30 mg/kg, IP), or naltrindole (0-10 mg/kg, IP) on ethanol consumption was measured in high- and low-ethanol-consuming rats with two different drinking paradigms. SoRI-9409-, naltrexone-, and naltrindole-mediated inhibition of DOP-R-stimulated [(35)S]GTP gamma S binding was measured in brain membranes prepared from high-ethanol-consuming rats. The effects of SoRI-9409 on morphine-mediated analgesia, conditioned place preference, and anxiety were also examined. In high- but not low-ethanol-consuming animals, SoRI-9409 is threefold more effective and selective at reducing ethanol consumption when compared with naltrexone or naltrindole for up to 24 hours. SoRI-9409 administered daily for 28 days continuously reduced ethanol consumption, and when the administration of SoRI-9409 was terminated, the amount of ethanol consumed remained lower compared with vehicle-treated animals. Furthermore, SoRI-9409 inhibits DOP-R-stimulated [(35)S]GTP gamma S binding in brain membranes of high-ethanol-consuming rats. SoRI-9409 causes selective and long-lasting reductions of ethanol consumption. This suggests that compounds that have high affinity for DOP-Rs such as SoRI-9409 might be promising candidates for development as a novel therapeutic for the treatment of alcoholism.

Novel cleavage reaction of the C16–N17 bond in naltrexone derivatives

A dealkylation reaction of tertiary amines using chloroformate was a useful method for synthesizing morphinan derivatives without 17-substituents; however, the reaction has been applied to only the 14-hydromorphinans. In the course of the investigation of the 17-dealkylation reaction in 14-hydroxymorphinan, the novel cleavage reaction of the C16–N17 bond in the naltrexone derivative was found. A plausible reaction mechanism based on the stereoelectronic effect is presented. The examinations of dealkylation reactions in general tertiary amines ranked the tendency of cleavage as follows: benzyl>cyclopropylmethyl (CPM)≈allyl>methyl, ethyl. The preferable cleavage of the CPM group may be explained by the polarization of CPM–N17 bond due to a postulation of extreme stability of the cyclopropylcarbinyl cation.

Synthesis of N-isobutylnoroxymorphone from naltrexone by a selective cyclopropane ring opening reaction

Selective ring opening reaction of the N-cyclopropylmethyl group in naltrexone ( 1d) was effected in the presence of platinum (IV) oxide and hydrobromic acid under a hydrogen atmosphere at rt to selectively afford N-isobutyl derivative 10. The binding affinity of N- i-Bu derivative 10 for opioid receptors was 11–17 times less than that of the corresponding N-CPM compound, naltrexone ( 1d). However, compound 10 showed dose-dependent analgesic effects. Contrary to expectations based on previous structure–activity relationship studies for a series of N-substituted naltrexone derivatives that compound 10 would be an opioid antagonist, 10 showed dose-dependent analgesia in the mouse acetic acid writhing test (ED 50: 5.05 mg/kg, sc), indicating it was an opioid agonist. This finding may have a great influence on the drug design of opioid agonists.

Methylnaltrexone Mechanisms of Action and Effects on Opioid Bowel Dysfunction and Other Opioid Adverse Effects

To review the mechanisms of action of methylnaltrexone and its effects on opioid bowel dysfunction, as well as its effects on other opioid-induced adverse effects (ADEs), and its potential roles in clinical practice. A literature search using the MEDLINE and Cochrane Collaboration databases for articles published between 1966 and March 2007 was performed. Additional data sources were obtained from manual searches of recent journal articles, book chapters, and monographs. An updated literature search showed no additional publications. Abstracts and original preclinical and clinical research reports published in the English language were identified for review. Review articles, commentaries, and news reports of this compound were excluded. Literature related to opioids, opioid receptors, opioid antagonists, methylnaltrexone, opioid-induced bowel dysfunction, constipation, nausea, and vomiting was evaluated and selected based on consideration of the support shown for the proof of concept, mechanistic findings, and timeliness. Fifty-eight original articles from preclinical studies and clinical trials using methylnaltrexone were identified. Pharmacologic action, benefits, and ADEs of methylnaltrexone were reviewed, with a focus on its effects on bowel dysfunction after opioids. Emphases were placed on its receptor binding activities and therapeutically relevant sites of action (peripheral vs central), in which peripheral opioid receptors in the body contribute to physiological and drug-induced effects. Morphine and related opioids are associated with a number of limiting ADEs, including opioid-induced bowel dysfunction. Methylnaltrexone, a quaternary derivative of naltrexone, blocks peripheral effects of opioids while sparing central analgesic effects. It is currently under late-stage clinical investigation for the treatment of opioid-induced constipation in patients with advanced illness. Reported results showed the drug to be generally well-tolerated. The rapid reversal of constipation is very encouraging. Hastening postoperative discharge may also be possible. Methylnaltrexone has the potential to prevent or treat opioid-induced peripherally mediated ADEs on bowel dysfunction without interfering with central analgesia. The study of methylnaltrexone leads to a greater understanding of the mechanisms of action of opioid pharmacology.

Methylnaltrexone, a novel peripheral opioid receptor antagonist for the treatment of opioid side effects

Methylnaltrexone is an investigational peripheral opioid receptor antagonist, a quaternary derivative of naltrexone. Methylnaltrexone has greater polarity and lower lipid solubility, thus it does not cross the blood–brain barrier in humans. Methylnaltrexone offers the therapeutic potential to block or reverse the undesired side effects of opioids that are mediated by receptors located in the periphery (e.g., in the gastrointestinal tract), without affecting analgesia or precipitating the opioid withdrawal symptoms that are predominantly mediated by receptors in the CNS. This article reviews preclinical studies and clinical opioid bowel dysfunction trial data, and briefly discusses other potential roles of this compound in clinical practice.

Potentiation of rat lymphocyte proliferation by novel non-peptidic synthetic opioids

Opioids represent a major source of relief for acute and chronic, moderate to severe nonmalignant pain. However, opioid abuse may cause immunosuppression leading to infections and cancer development. Recently we reported results on novel non-peptidic delta- and mu-selective opioids that induced immunopotentiation in vitro and ex vivo. In the present study, we investigated the effects of the delta agonist SNC 80, and mu agonists, naltrindole and naltrexone derivatives for their capacity to alter lymphoproliferation in vitro. They were observed to stimulate lymphoproliferation at concentrations ranging from 10 − 10 to 10 − 5 M. SNC 80 significantly ( p < 0.05) stimulated (43–311%) proliferation of resident and concanavalin A (Con A)-treated lymphocytes; the naltrindole derivatives 9332 and 9333 caused significant ( p < 0.05) 26–47% and 13–43%, respectively, stimulation of Con A-treated lymphoproliferation; whereas the naltrexone derivatives 9334 and 9336 significantly ( p < 0.05) stimulated 9–40% and 15–69%, respectively, proliferation of resident and Con A-treated lymphocytes. These novel opioid ligands could serve as immunotherapeutic agents by increasing the pool of lymphocytes with potential use in the treatment of infectious diseases including AIDS. This study provides evidence of the relationship structure/function of opioids on lymphoproliferation, and supports further evaluation of opioids with immunomodulatory potential in preclinical and clinical studies.

Syntheses and receptor-binding studies of derivatives of the opioid antagonist naltrexone

Naltrexone (1), which is a member of the group of competitive opioid antagonists, shows a strong affinity for μ-receptors and its derivatives have been notable as novel receptor anatgonists. In this paper, the preparation of several naltrexone derivatives is described; these were used to investigate the role of the oxygenated functional groups in facilitating binding to a series of the opioid receptors. The derivatives showed affinity for opioid μ-receptors which was similar to that of naltrexone, but these compounds, which had masked hydroxyl functional groups, displayed a moderate activity. These results suggest that every oxygenated functional group in naltrexone (1) plays an important role in binding to the opioid receptor.

A Review of the Potential Role of Methylnaltrexone in Opioid Bowel Dysfunction

Opioids are widely used analgesics in patients with advanced cancer. However, their effectiveness for pain relief is often limited by the most frequently occurring side effect, opioid bowel dysfunction (OBD). Because conventional laxation measures are often ineffective in treating OBD, alternative approaches need to be investigated. Opioid action on the gut appears to be mediated mainly by receptors in the gastrointestinal (GI) tract rather than by those in the central nervous system (CNS). Opioid antagonists, such as naloxone, naltrexone, and nalmefene, have been studied as a means of antagonizing the peripheral effects of opioids, but these agents can enter the CNS and reverse analgesia or cause opioid withdrawal symptoms. Methylnaltrexone (MNTX) is a novel quaternary derivative of naltrexone that does not cross the blood–brain barrier and acts as a selective peripheral opioid receptor antagonist. In normal volunteers, intravenous or oral MNTX reverses opioid-induced reduction in bowel motility without affecting analgesia. Bioavailability of MNTX is low after oral administration, and plasma levels do not correlate with its actions in the gut, suggesting a predominantly local luminal action of MNTX on the gut. In patients receiving long-term opioid therapy, MNTX administered intravenously or orally was effective in reducing the delay in oral-cecal transit and eliciting laxation responses in all subjects without causing withdrawal symptoms. MNTX is a peripherally selective opioid antagonist that may have clinical utility in managing OBD with minimal adverse effects.