Reinforcing effects of fentanyl analogs found in illicit drug markets.

RATIONALE: The potent synthetic opioid fentanyl, and its analogs, continue to drive opioid-related overdoses. Although the pharmacology of fentanyl is well characterized, there is little information about the reinforcing effects of clandestine fentanyl analogs (FAs). OBJECTIVES: Here, we compared the effects of fentanyl and the FAs acetylfentanyl, butyrylfentanyl, and cyclopropylfentanyl on drug self-administration in male and female rats. These FAs feature chemical modifications at the carbonyl moiety of the fentanyl scaffold. METHODS: Sprague-Dawley rats fitted with intravenous jugular catheters were placed in chambers containing two nose poke holes. Active nose poke responses resulted in drug delivery (0.2 mL) over 2 s on a fixed-ratio 1 schedule, followed by a 20 s timeout. Acquisition doses were 0.01 mg/kg/inj for fentanyl and cyclopropylfentanyl, and 0.03 mg/kg/inj for acetylfentanyl and butyrylfentanyl. After 10 days of acquisition, dose-effect testing was carried out, followed by 10 days of saline extinction. RESULTS: Self-administration of fentanyl and FAs was acquired by both male and female rats, with no sex differences in acquisition rate. Fentanyl and FAs showed partial inverted-U dose-effect functions; cyclopropylfentanyl and fentanyl had similar potency, while acetylfentanyl and butyrylfentanyl were less potent. Maximal response rates were similar across drugs, with fentanyl and cyclopropylfentanyl showing maximum responding at 0.001 mg/kg/inj, acetylfentanyl at 0.01 mg/kg/inj, and butyrylfentanyl at 0.003 mg/kg/inj. No sex differences were detected for drug potency, efficacy, or rates of extinction. CONCLUSIONS: Our work provides new evidence that FAs display significant abuse liability in male and female rats, which suggests the potential for compulsive use in humans.

Endogenous opiates and behavior: 2023.

This paper is the forty-sixth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2023 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug and alcohol abuse (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).

Bispecific Sigma1R-Antagonist/MOR-Agonist Compounds for Pain.

Recent research has significantly advanced an understanding of sigma receptors, which consist of two distinct subtypes designated as S1R and S2R (s1R and s2R gene products, respectively). Both subtypes have recently been cloned and their crystal structures have been published. As a result, highly selective S1R and S2R agonist and antagonist ligands are now available. Unlike the confusion generated from prior use of non-selective 'sigma' compounds, these tool compounds have begun to add clarity about the function of sigma receptors in health and disease.  The discovery of compounds with high-affinity (nM range) S1R/S2R or S2R/S1R subtype selectivity (>100-fold), and selectivity over off-target sites (>1,000-fold) has brought the study of sigma receptor pharmacology into the modern era. Computer modeling has contributed to a better understanding of the binding processes, structural requirements for chemical synthesis, and potential therapeutic uses. Several lines of evidence converge on pain as a therapeutic target for S1R-antagonists (as single mechanism or as part of a multi-mechanistic approach). We highlight here some compounds reported over the past few years that have promise for use as analgesics, specifically some mono-mechanistic S1R-antagonists, and some that are 'bispecific', i.e., have more than one mechanism of action, for example, complementary action of the mu-opioid receptor (MOR). We concentrate on some compounds that are further along in development, in particular, some of the bispecific S1R-antagonist/MOR-agonist compounds.

Pharmacologic profile of ITI-333: a novel molecule for treatment of substance use disorders.

RATIONALE: Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is a novel molecule in development for treatment of substance use disorders, psychiatric comorbidities, and pain. OBJECTIVE: Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays. METHODS: Cell-based assays were used to measure receptor binding and intrinsic efficacy of ITI-333; animal models were employed to assess effects on opioid reinstatement, precipitated oxycodone withdrawal, and drug abuse liability. RESULTS: In vitro, ITI-333 is a potent 5-HT2A receptor antagonist (Ki = 8 nM) and a biased, partial agonist at µ-opioid (MOP) receptors (Ki = 11 nM; lacking ß-arrestin agonism) with lesser antagonist activity at adrenergic α1A (Ki = 28 nM) and dopamine D1 (Ki = 50 nM) receptors. In vivo, ITI-333 blocks 5-HT2A receptor-mediated head twitch and MOP receptor-mediated effects on motor hyperactivity in mice. ITI-333 alone is a naloxone-sensitive analgesic (mice) which suppresses somatic signs of naloxone-precipitated oxycodone withdrawal (mice) and heroin cue-induced reinstatement responding without apparent tolerance or physical dependence after chronic dosing (rats). ITI-333 did not acutely impair gastrointestinal or pulmonary function (rats) and was not intravenously self-administered by heroin-maintained rats or rhesus monkeys. CONCLUSIONS: ITI-333 acts as a potent 5-HT2A receptor antagonist, as well a biased MOP receptor partial agonist with low intrinsic efficacy. ITI-333 mitigates opioid withdrawal/reinstatement, supporting its potential utility as a treatment for OUD.

Buprenorphine Use for Analgesia in Palliative Care.

Buprenorphine is a semi-synthetic long-acting partial µ-opioid receptor (MOR) agonist that can be used for chronic pain as a sublingual tablet, transdermal patch (Butrans®), or a buccal film (Belbuca®). Buprenorphine's unique high receptor binding affinity and slow dissociation at the MOR allow for effective analgesia while offering less adverse effects compared to a full agonist opioid, in particular, less concern for respiratory depression and constipation. It is underused in chronic pain and palliative care due to misconceptions and stigma from its use in opioid use disorder (OUD). This case report discusses the unique pharmacology of buprenorphine, including its advantages, disadvantages, available formulations, drug-drug interactions, initiation and conversion strategies, and identifies ideal populations for use, especially within the palliative care patient population.

Cholinergic mu-opioid receptor deletion alters reward preference and aversion-resistance.

The endogenous opioid system has been implicated in alcohol consumption and preference in both humans and animals. The mu opioid receptor (MOR) is expressed on multiple cells in the striatum, however little is known about the contributions of specific MOR populations to alcohol drinking behaviors. The current study used mice with a genetic deletion of MOR in cholinergic cells (ChAT-Cre/Oprm1fl/fl) to examine the role of MORs expressed in cholinergic interneurons (CINs) in home cage self-administration paradigms. Male and female ChAT-Cre/Oprm1fl/fl mice were generated and heterozygous Cre+ (knockout) and Cre- (control) mice were tested for alcohol consumption in two drinking paradigms: limited access "Drinking in the Dark" and intermittent access. Quinine was added to the drinking bottles in the DID experiment to test aversion-resistant, "compulsive" drinking. Nicotine and sucrose drinking were also assessed so comparisons could be made with other rewarding substances. Cholinergic MOR deletion did not influence consumption or preference for ethanol (EtOH) in either drinking task. Differences were observed in aversion-resistance in males with Cre + mice tolerating lower concentrations of quinine than Cre-. In contrast to EtOH, preference for nicotine was reduced following cholinergic MOR deletion while sucrose consumption and preference was increased in Cre+ (vs. Cre-) females. Locomotor activity was also greater in females following the deletion. These results suggest that cholinergic MORs participate in preference for rewarding substances. Further, while they are not required for consumption of alcohol alone, cholinergic MORs may influence the tendency to drink despite negative consequences.

Blocking potential metabolic sites on NAT to improve its safety profile while retaining the pharmacological profile.

The number of opioid-related overdose deaths and individuals that have suffered from opioid use disorders have significantly increased over the last 30 years. FDA approved maintenance therapies to treat opioid use disorder may successfully curb drug craving and prevent relapse but harbor adverse effects that reduce patient compliance. This has created a need for new chemical entities with improved patient experience. Previously our group reported a novel lead compound, NAT, a mu-opioid receptor antagonist that potently antagonized the antinociception of morphine and showed significant blood-brain barrier permeability. However, NAT belongs to thiophene containing compounds which are known structural alerts for potential oxidative metabolism. To overcome this, 15 NAT derivatives with various substituents at the 5'-position of the thiophene ring were designed and their structure-activity relationships were studied. These derivatives were characterized for their binding affinity, selectivity, and functional activity at the mu opioid receptor and assessed for their ability to antagonize the antinociceptive effects of morphine in vivo. Compound 12 showed retention of the basic pharmacological attributes of NAT while improving the withdrawal effects that were experienced in opioid-dependent mice. Further studies will be conducted to fully characterize compound 12 to examine whether it would serve as a new lead for opioid use disorder treatment and management.

Successful Use of Intravenous Methylnaltrexone for Opioid-Induced Constipation in Critically Ill Pediatric Patients.

Objectives Methylnaltrexone is U.S. Food and Drug Administration (FDA) approved as a subcutaneous injection for adults with opioid-induced constipation (OIC). Case series have described the use of methylnaltrexone for OIC in the pediatric oncology population. There are limited data describing its intravenous use in critically ill pediatric patients. Methods We conducted a retrospective observational study at St. Louis Children's Hospital. Patients less than 18 years old who received at least one dose of intravenous methylnaltrexone while admitted to an intensive care unit between January 2016 and August 2019 were included. The primary outcome was documented laxation within 24 hours of methylnaltrexone administration. Results Sixteen patients received a total of 34 doses of intravenous methylnaltrexone. Patients received a median of 1.69 (interquartile range [IQR], 0.9-4.86) morphine milligram equivalents per kilogram per 24 hours, over a median of 14 days (IQR, 11-30), before methylnaltrexone administration. The median dose of methylnaltrexone was 0.15 mg/kg (IQR, 0.15-0.16). Ten patients (63%) responded to the first dose of methylnaltrexone, and 14 patients (88%) responded to at least one dose. Overall, 26 doses (76%) led to patient response. Four patients (25%) experienced adverse events (emesis, abdominal pain) after methylnaltrexone administration. No signs or symptoms of opioid withdrawal were documented. Conclusions Intravenous methylnaltrexone appears to be safe and effective in treating OIC in critically ill pediatric patients. No serious adverse events or signs of opioid withdrawal were observed after single and repeat dosing. Patients responded to methylnaltrexone with varying opioid dosing and durations prior to administration.

IUPHAR review: Recent progress in the development of Mu opioid receptor modulators to treat opioid use disorders.

Opioid Use Disorder (OUD) can be described as intense preoccupation with using or obtaining opioids despite the negative consequences associated with their use. As the number of OUD cases in the U.S. increase, so do the number of opioid-related overdose deaths. In 2022, opioid-related overdose became the No. 1 cause of death for individuals in the U.S. between the ages of 25 and 64 years of age. Because of the introduction of highly potent synthetic opioids (e.g. fentanyl) to the illicit drug market, there is an urgent need for therapeutics that successfully reduce the number of overdoses and can help OUD patients maintain sobriety. Most abused opioids stimulate the mu-opioid receptor (MOR) and activation of this receptor can lead to positive (e.g., euphoria) consequences. However, the negative side effects of MOR stimulation can be fatal (e.g., sedation, respiratory depression). Therefore, the MOR is an attractive target for developing medications to treat OUD. Current FDA drugs include MOR agonists that aid in detoxification and relapse prevention, and MOR antagonists that also serve as maintenance therapies or reverse overdose. These medications are limited by their abuse potential, adverse effects, or pharmacological profiles which leaves ample room for research into designing new chemical entities with optimal physiological effects. These includes, orthosteric ligands that target the primary binding site of the MOR, allosteric ligands that positively, negatively, or "silently" modulate receptor function, and lastly, bitopic ligands target both the orthosteric and allosteric sites simultaneously.

Disinhibition does not play a role in endomorphin-2-induced changes in inspiratory motoneuron output produced by in vitro neonatal rat preparations.

Low level activation of mu-opioid receptors (MORs) in neonatal rat brainstem-spinal cord preparations increases inspiratory burst amplitude recorded on cervical spinal roots. We tested whether: (1) MOR activation with an endogenous ligand, such as endomorphin-2, increases inspiratory burst amplitude, (2) disinhibition of GABAergic or glycinergic inhibitory synaptic transmission is involved, and (3) inflammation alters endomorphin-2 effects. Using neonatal rat (P0-P3) brainstem-spinal cord preparations, bath-applied endomorphin-2 (10-200 nM) increased inspiratory burst amplitude and decreased burst frequency. Blockade of GABAA receptors (picrotoxin), glycine receptors (strychnine), or both (picrotoxin and strychnine) did not abolish endomorphin-2-induced effects. In preparations isolated from neonatal rats injected 3 h previously with lipopolysaccharide (LPS, 0.1 mg/kg), endomorphin-2 continued to decrease burst frequency but abolished the burst amplitude increase. Collectively, these data indicate that disinhibition of inhibitory synaptic transmission is unlikely to play a role in endomorphin-2-induced changes in inspiratory motor output, and that different mechanisms underlie the endomorphin-2-induced increases in inspiratory burst amplitude and decreases in burst frequency.

Epigenetic regulation in opioid induced hyperalgesia.

About 25 million American adults experience pain daily and one of the most commonly prescribed drugs to treat pain are opioids. Prolonged opioid usage and dose escalations can cause a paradoxical response where patients experience enhanced pain sensitivity. This opioid induced hyperalgesia (OIH) is a major hurdle when treating pain in the clinic because its underlying mechanisms are still not fully understood. OIH is also commonly overlooked and lacks guidelines to prevent its onset. Research on pain disorders and opioid usage have recognized potential epigenetic drivers of disease including DNA methylation, histone modifications, miRNA regulation, but their involvement in OIH has not been well studied. This article discusses epigenetic changes that may contribute to pathogenesis, with an emphasis on miRNA alterations in OIH. There is a crucial gap in knowledge including how multiple epigenetic modulators contribute to OIH. Elucidating the epigenetic changes underlying OIH and the crosstalk among these mechanisms could lead to the development of novel targets for the prevention and treatment of this painful phenomena.

Opioid Mechanisms and the Treatment of Depression.

Opioid receptors are widely expressed in the brain, and the opioid system has a key role in modulating mood, reward processing and stress responsivity. There is mounting evidence that the endogenous opioid system may be dysregulated in depression and that drug treatments targeting mu, delta and kappa opioid receptors may show antidepressant potential. The mechanisms underlying the therapeutic effects of opioid system engagement are complex and likely multi-factorial. This chapter explores various pathways through which the modulation of the opioid system may influence depression. These include impacts on monoaminergic systems, the regulation of stress and the hypothalamic-pituitary-adrenal axis, the immune system and inflammation, brain-derived neurotrophic factors, neurogenesis and neuroplasticity, social pain and social reward, as well as expectancy and placebo effects. A greater understanding of the diverse mechanisms through which opioid system modulation may improve depressive symptoms could ultimately aid in the development of safe and effective alternative treatments for individuals with difficult-to-treat depression.

Identification and Pharmacological Characterization of a Low-Liability Antinociceptive Bifunctional MOR/DOR Cyclic Peptide.

Peptide-based opioid ligands are important candidates for the development of novel, safer, and more effective analgesics to treat pain. To develop peptide-based safer analgesics, we synthesized a mixture-based cyclic pentapeptide library containing a total of 24,624 pentapeptides and screened the mixture-based library samples using a 55 °C warm water tail-withdrawal assay. Using this phenotypic screening approach, we deconvoluted the mixture-based samples to identify a novel cyclic peptide Tyr-[D-Lys-Dap(Ant)-Thr-Gly] (CycloAnt), which produced dose- and time-dependent antinociception with an ED50 (and 95% confidence interval) of 0.70 (0.52-0.97) mg/kg i.p. mediated by the mu-opioid receptor (MOR). Additionally, higher doses (≥3 mg/kg, i.p.) of CycloAnt antagonized delta-opioid receptors (DOR) for at least 3 h. Pharmacological characterization of CycloAnt showed the cyclic peptide did not reduce breathing rate in mice at doses up to 15 times the analgesic ED50 value, and produced dramatically less hyperlocomotion than the MOR agonist, morphine. While chronic administration of CycloAnt resulted in antinociceptive tolerance, it was without opioid-induced hyperalgesia and with significantly reduced signs of naloxone-precipitated withdrawal, which suggested reduced physical dependence compared to morphine. Collectively, the results suggest this dual MOR/DOR multifunctional ligand is an excellent lead for the development of peptide-based safer analgesics.

Monoclonal antibody targeting mu-opioid receptor attenuates morphine tolerance via enhancing morphine-induced receptor endocytosis.

Morphine is a frequently used analgesic that activates the mu-opioid receptor (MOR), which has prominent side effects of tolerance. Although the inefficiency of morphine in inducing the endocytosis of MOR underlies the development of morphine tolerance, currently, there is no effective therapy to treat morphine tolerance. In the current study, we aimed to develop a monoclonal antibody (mAb) precisely targeting MOR and to determine its therapeutic efficacy on morphine tolerance and the underlying molecular mechanisms. We successfully prepared a mAb targeting MOR, named 3A5C7, by hybridoma technique using a strategy of deoxyribonucleic acid immunization combined with cell immunization, and identified it as an immunoglobulin G mAb with high specificity and affinity for MOR and binding ability to antigens with spatial conformation. Treatment of two cell lines, HEK293T and SH-SY5Y, with 3A5C7 enhanced morphine-induced MOR endocytosis via a G protein-coupled receptor kinase 2 (GRK2)/ß-arrestin2-dependent mechanism, as demonstrated by immunofluorescence staining, flow cytometry, Western blotting, coimmunoprecipitation, and small interfering ribonucleic acid (siRNA)-based knockdown. This mAb also allowed MOR recycling from cytoplasm to plasma membrane and attenuated morphine-induced phosphorylation of MOR. We established an in vitro morphine tolerance model using differentiated SH-SY5Y cells induced by retinoic acid. Western blot, enzyme-linked immunosorbent assays, and siRNA-based knockdown revealed that 3A5C7 mAb diminished hyperactivation of adenylate cyclase, the in vitro biomarker of morphine tolerance, via the GRK2/ß-arrestin2 pathway. Furthermore, in vivo hotplate test demonstrated that chronic intrathecal administration of 3A5C7 significantly alleviated morphine tolerance in mice, and withdrawal jumping test revealed that both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence. Finally, intrathecal electroporation of silencing short hairpin RNA illustrated that the in vivo anti-tolerance and anti-dependence efficacy of 3A5C7 was mediated by enhanced morphine-induced MOR endocytosis via GRK2/ß-arrestin2 pathway. Collectively, our study provided a therapeutic mAb, 3A5C7, targeting MOR to treat morphine tolerance, mediated by enhancing morphine-induced MOR endocytosis. The mAb 3A5C7 demonstrates promising translational value to treat clinical morphine tolerance.

Naloxegol versus Methylnaltrexone for Opioid-Induced Constipation in Critically Ill Patients.

BACKGROUND: Constipation impacts 58% to 83% of critically ill patients and is associated with increased time on mechanical ventilation, delirium, and increased length of stay (LOS) in the intensive care unit (ICU). OBJECTIVE: The purpose of this study was to evaluate the efficacy of enteral naloxegol (NGL) versus subcutaneous methylnaltrexone (MNTX) for the management of opioid-induced constipation (OIC) in critically ill patients. METHODS: A retrospective analysis was conducted on adult patients admitted to the ICU who received a parenteral opioid infusion for at least 4 hours and experienced no bowel movement (BM) within the 48-hour period preceding the administration of NGL or MNTX. The primary outcome was time to first BM from the start of NGL or MNTX therapy. Secondary outcomes included number of BMs 72 hours following NGL or MNTX administration, ICU LOS, and cost-effectiveness. RESULTS: After exclusion criteria were applied, 110 and 51 patients were included in the NGL and MNTX groups, respectively. With a 10% noninferiority margin, NGL was noninferior to MNTX (Wald statistic = 1.67; P = 0.047). Median time to first BM was 23.7 hours for NGL and 18.3 hours for MNTX patients. Median LOS was 14 days (NGL) and 12 days (MNTX), and the average number of BMs in 72 hours was 3.9 for NGL and 3.8 for MNTX. Using wholesale acquisition cost (WAC), the cost per BM for NGL and MNTX was $21.74 and $170.00, respectively. CONCLUSION AND RELEVANCE: This study determined that NGL and MNTX had similar time to BM. NGL appears to be a safe and effective alternative with cost-saving potential in treating OIC in critically ill patients.

A new formulation of dezocine, Cyc-dezocine, reduces oxycodone self-administration in female and male rats.

Dezocine is a partial mu opioid receptor agonist previously used as an analgesic for perioperative acute pain in the US and is now the most used perioperative analgesic in China. In general, dezocine is well-tolerated, with relatively minimal risk of fatal respiratory depression. To our knowledge, there are no reports of dezocine addiction, which suggests that the abuse liability of dezocine is low. The overarching goal of this study was to determine the efficacy of a novel formulation of dezocine (Cyc-dezocine), developed for intraperitoneal or intranasal administration, to reduce voluntary opioid taking in rats. One cohort of male rats self-administered intravenous oxycodone on a fixed-ratio 5 schedule of reinforcement. Once oxycodone taking stabilized, rats were pretreated with systemic injections of vehicle or Cyc-dezocine. Cyc-dezocine dose-dependently reduced intravenous oxycodone self-administration. A second cohort of male and female rats self-administered oral oxycodone from drinking water. Once oxycodone taking stabilized, rats were pretreated with intra-nasal Cyc-dezocine. Consistent with the effects of i.p. Cyc-dezocine in our intravenous oxycodone studies, intra-nasal Cyc-dezocine attenuated oral oxycodone self-administration. Together, these findings support the need for further studies investigating the therapeutic potential of Cyc-dezocine for treating opioid use disorder.

The effect of morphine on rat microglial phagocytic activity: An in vitro study of brain region-, plating density-, sex-, morphine concentration-, and receptor-dependency.

Opioids have long been used for clinical pain management, but also have addictive properties that have contributed to the ongoing opioid epidemic. While opioid activation of opioid receptors is well known to contribute to reward and reinforcement, data now also suggest that opioid activation of immune signaling via toll-like receptor 4 (TLR4) may also play a role in addiction-like processes. TLR4 expression is enriched in immune cells, and in the nervous system is primarily expressed in microglia. Microglial phagocytosis is important for developmental, homeostatic, and pathological processes. To examine how morphine impacts microglial phagocytosis, we isolated microglia from adult male and female rat cortex and striatum and plated them in vitro at 10,000 (10K) or 50,000 cells/well densities. Microglia were incubated with neutral fluorescent microbeads to stimulate phagocytosis in the presence of one of four morphine concentrations. We found that the brain region from which microglia are isolated and plating density, but not morphine concentration, impacts cell survival in vitro. We found that 10-12 M morphine, but not higher concentrations, increases phagocytosis in striatal microglia in vitro independent of sex and plating density, while 10-12 M morphine increased phagocytosis in cortical microglia in vitro independent of sex, but contingent on a plating density. Finally, we demonstrate that the effect of 10-12 M morphine in striatal microglia plated at 10 K density is mediated via TLR4, and not µORs. Overall, our data suggest that in rats, a morphine-TLR4 signaling pathway increases phagocytic activity in microglia independent of sex. This may is useful information for better understanding the possible neural outcomes associated with morphine exposures.

Methylnaltrexone Treatment for Opioid-Induced Constipation in Patients with and without Cancer: Effect of Initial Dose.

Purpose: Opioid-induced constipation (OIC) is a common side effect of opioid therapy. Methylnaltrexone (MNTX) is a selective, peripherally acting µ-opioid receptor antagonist, with demonstrated efficacy in treating OIC. We pooled results from MNTX clinical trials to compare responses to an initial dose in patients with chronic cancer and noncancer pain. Patients and Methods: This post hoc analysis used pooled data from 3 randomized, placebo-controlled studies of MNTX in patients with advanced illness with OIC. Assessments included the proportions of patients achieving rescue-free laxation (RFL) within 4 and 24 hours of the first study drug dose, time to RFL, current and worst pain intensity, and adverse events, stratified by the presence/absence of cancer. Results: A total of 355 patients with cancer (MNTX n = 198, placebo n = 157) and 163 without active cancer (MNTX n = 83; placebo n = 80) were included. More patients treated with MNTX compared with those who received placebo achieved an RFL within 4 (cancer: MNTX, 61.1% vs placebo,15.3%, p<0.0001; noncancer: MNTX, 62.2% vs placebo, 17.5%, p<0.0001) and 24 hours (cancer: MNTX, 71.2% vs placebo, 41.4%, p<0.0001; noncancer: MNTX, 74.4% vs placebo, 37.5%, p<0.0001) of the initial dose. Cumulative RFL response rates within 4 hours of the first, second, or third dose of study drug were also higher in MNTX-treated patients. The estimated time to RFL was shorter among those who received MNTX and similar in cancer and noncancer patients. Mean pain scores declined similarly in all groups. The most common adverse events in both cancer and noncancer patients were abdominal pain, flatulence, and nausea. Conclusion: After the first dose, MNTX rapidly induced a laxation response in the majority of both cancer and noncancer patients with advanced illness. Opioid-induced analgesia was not compromised, and adverse events were primarily gastrointestinal in nature. Methylnaltrexone is a well-tolerated and effective treatment for OIC in both cancer and noncancer patients.

Discovery and structure-activity relationships (SAR) of a novel class of 2-substituted N-piperidinyl indole-based nociceptin opioid receptor ligands.

The development of SAR around substituted N-piperidinyl indole-based nociceptin opioid receptor (NOP) ligands led to the discovery of a novel series of 2-substituted N-piperidinyl indoles that provide both selective NOP full agonists and bifunctional NOP full agonists-µ opioid (MOP) receptor partial agonists. 2-substituted N-piperidinyl indoles have improved potency at the NOP receptor and are NOP full agonists, compared to our previously reported 3-substituted N-piperidinyl indoles that are selective NOP partial agonists. SAR in this series of 2-substituted N-piperidinyl indoles shows that 2-substitution versus 3-substitution on the indole moiety affects their intrinsic activity and opioid receptor selectivity. Molecular docking of these 2-substituted N-piperidinyl indoles in an active-state NOP homology model and MOP receptor structures provides a rationale for the differences observed in the binding, functional profiles and selectivity of 2-substituted versus 3-substituted N-piperidinyl indoles.