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Journal of Medicinal Chemistry Jun 2024Development of more efficacious medications with improved safety profiles to manage and treat multiple forms of pain is a critical element of healthcare. To this end, we...
Development of more efficacious medications with improved safety profiles to manage and treat multiple forms of pain is a critical element of healthcare. To this end, we have designed and synthesized a novel class of tetracyclic pyridopyrroloquinoxalinone derivatives with analgesic properties. The receptor binding profiles and analgesic properties of these tetracyclic compounds were studied. Systematic optimizations of this novel scaffold culminated in the discovery of the clinical candidate, (6,10)-8-[3-(4-fluorophenoxy)propyl]-6,7,8,9,10,10-hexahydro-1-pyrido[3',4':4,5]pyrrolo[1,2,3-]quinoxalin-2(3)-one (compound , ITI-333), which exhibited potent binding affinity to serotonin 5-HT ( = 8.3 nM) and μ-opioid receptors (MOR, = 11 nM) and moderate affinity to adrenergic α ( = 28 nM) and dopamine D ( = 50 nM) receptors. ITI-333 acts as a 5-HT receptor antagonist, a MOR partial agonist, and an adrenergic α receptor antagonist. ITI-333 exhibited dose-dependent analgesic effects in rodent models of acute pain. Currently, this investigational new drug is in phase I clinical development.
Topics: Animals; Humans; Analgesics; Structure-Activity Relationship; Administration, Oral; Pain; Mice; Male; Rats; Drug Discovery; Rats, Sprague-Dawley; Biological Availability; Receptors, Opioid, mu; Pyridines; Pyrroles
PubMed: 38805667
DOI: 10.1021/acs.jmedchem.4c00480 -
Pharmacy (Basel, Switzerland) May 2024Buprenorphine 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...
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.
PubMed: 38804470
DOI: 10.3390/pharmacy12030078 -
Cell Death Discovery May 2024Despite the success in treating newly diagnosed pediatric acute lymphoblastic leukemia (aLL), the long-term cure rate for the 20% of children who relapse is poor, making...
Despite the success in treating newly diagnosed pediatric acute lymphoblastic leukemia (aLL), the long-term cure rate for the 20% of children who relapse is poor, making relapsed aLL the primary cause of cancer death in children. By unbiased genome-wide retroviral RNAi screening and knockdown studies, we previously discovered opioid receptor mu 1 (OPRM1) as a new aLL cell resistance biomarker for the aLL chemotherapeutic drug, L-asparaginase, i.e., OPRM1 loss triggers L-asparaginase resistance. Indeed, aLL cell OPRM1 level is inversely proportional to L-asparaginase IC50: the lower the OPRM1 level, the higher the L-asparaginase IC50, indicating that aLL cells expressing reduced OPRM1 levels show resistance to L-asparaginase. In the current study, we utilized OPRM1-expressing and -knockdown aLL cells as well as relapsed patient aLL cells to identify candidate targeted therapy for L-asparaginase-resistant aLL. In OPRM1-expressing cells, L-asparaginase induces apoptosis via a cascade of events that include OPRM1-mediated decline in [cAMP], downregulation of PKA-mediated BAD S phosphorylation that can be reversed by 8-CPT-cAMP, cyt C release from the mitochondria, and subsequent caspase activation and PARP1 cleavage. The critical role of PKA inhibition due to a decrease in [cAMP] in this apoptotic process is evident in the killing of OPRM1-knockdown and low OPRM1-expressing relapsed patient aLL cells by the PKA inhibitors, H89 and 14-22 amide. These findings demonstrate for the first time that PKA can be targeted to kill aLL cells resistant to L-asparaginase due to OPRM1 loss, and that H89 and 14-22 amide may be utilized to destroy L-asparaginase-resistant patient aLL cells.
PubMed: 38802344
DOI: 10.1038/s41420-024-02028-w -
Journal of Psychiatry and Cognitive... 2024Opioid use disorder (OUD)-associated overdose deaths have reached epidemic proportions worldwide. An important driving force for relapse is anxiety associated with...
OBJECTIVES
Opioid use disorder (OUD)-associated overdose deaths have reached epidemic proportions worldwide. An important driving force for relapse is anxiety associated with opioid withdrawal. We hypothesized that our new technology, termed heterodyned whole-body vibration (HWBV) would ameliorate anxiety associated with OUD.
METHODS
Using a randomized, placebo (sham)-controlled, double-blind study design in an NIH-sponsored Phase 1 trial, we evaluated 60 male and 26 female participants diagnosed with OUD and undergoing treatment at pain and rehabilitation clinics. We utilized the Hamilton Anxiety Scale (HAM-A) and a daily visual analog scale anxiety rating (1-10) to evaluate anxiety. Subjects were treated for 10 min 5X/week for 4 weeks with either sham vibration (no interferential beat or harmonics) or HWBV (beats and harmonics). The participants also completed a neuropsychological test battery at intake and discharge.
RESULTS
In OUD subjects with moderate anxiety, there was a significant improvement in daily anxiety scores in the HWBV group compared to the sham treatment group (p=3.41 × 10). HAM-A scores in OUD participants at intake showed moderate levels of anxiety in OUD participants (HWBV group: 15.9 ± 1.6; Sham group: 17.8 ± 1.6) and progressively improved in both groups at discharge, but improvement was greater in the HWBV group (p=1.37 × 10). Furthermore, three indices of neuropsychological testing (mental rotations, spatial planning, and response inhibition) were significantly improved by HWBV treatment.
CONCLUSIONS
These findings support HWBV as a novel, non-invasive, non-pharmacological treatment for anxiety associated with OUD.
PubMed: 38798753
DOI: 10.29011/2574-7762.000073 -
BioRxiv : the Preprint Server For... May 202430% of people in the United States have diabetes or pre-diabetes. Many of these individuals will develop diabetic neuropathy as a comorbidity, which is often treated...
30% of people in the United States have diabetes or pre-diabetes. Many of these individuals will develop diabetic neuropathy as a comorbidity, which is often treated with exogenous opioids like morphine, oxycodone, or tramadol. Although these opioids are effective analgesics, growing evidence indicates that they may directly impact the endocrine pancreas function in human and preclinical models. One common feature of these exogenous opioid ligands is their preference for the mu opioid receptor (MOPR), so we aimed to determine if endogenous MOPRs directly regulate pancreatic islet metabolism and hormone secretion. We show that pharmacological antagonism of MOPRs enhances glucagon secretion, but not insulin secretion, from human islets under high glucose conditions. This increased secretion is accompanied by increased cAMP signaling. mRNA expression of MOPRs is enriched in human islet α-cells, but downregulated in T2D islet donors, suggesting a link between metabolism and MOPR expression. Conditional genetic knockout of MOPRs in murine α-cells increases glucagon secretion in high glucose conditions without increasing glucagon content. Consistent with downregulation of MOPRs during metabolic disease, conditional MOPR knockout mice treated with a high fat diet show impaired glucose tolerance, increased glucagon secretion, increased insulin content, and increased islet size. Finally, we show that MOPR-mediated changes in glucagon secretion are driven, in part, by KATP channel activity. Together, these results demonstrate a direct mechanism of action for endogenous opioid regulation of endocrine pancreas.
PubMed: 38798528
DOI: 10.1101/2024.05.13.593899 -
BioRxiv : the Preprint Server For... May 2024T cells have emerged as sex-dependent orchestrators of pain chronification but the sexually dimorphic mechanisms by which T cells control pain sensitivity is not...
T cells have emerged as sex-dependent orchestrators of pain chronification but the sexually dimorphic mechanisms by which T cells control pain sensitivity is not resolved. Here, we demonstrate an influence of regulatory T cells (Tregs) on pain processing that is distinct from their canonical functions of immune regulation and tissue repair. Specifically, meningeal Tregs (mTregs) express the endogenous opioid, enkephalin, and mTreg-derived enkephalin exerts an antinociceptive action through a presynaptic opioid receptor signaling mechanism that is dispensable for immunosuppression. mTregs are both necessary and sufficient for suppressing mechanical pain sensitivity in female but not male mice. Notably, the mTreg modulation of pain thresholds depends on sex-hormones and expansion of enkephalinergic mTregs during gestation imparts a remarkable pregnancy-induced analgesia in a pre-existing, chronic, unremitting neuropathic pain model. These results uncover a fundamental sex-specific, pregnancy-pronounced, and immunologically-derived endogenous opioid circuit for nociceptive regulation with critical implications for pain biology and maternal health.
PubMed: 38798460
DOI: 10.1101/2024.05.11.593442 -
BioRxiv : the Preprint Server For... May 2024Circuit influences on the midbrain dopamine system are crucial to adaptive behavior and cognition. Recent developments in the study of neuropeptide systems have enabled...
Circuit influences on the midbrain dopamine system are crucial to adaptive behavior and cognition. Recent developments in the study of neuropeptide systems have enabled high-resolution investigations of the intersection of neuromodulatory signals with basal ganglia circuitry, identifying the nociceptin/orphanin FQ (N/OFQ) endogenous opioid peptide system as a prospective regulator of striatal dopamine signaling. Using a prepronociceptin-Cre reporter mouse line, we characterized highly selective striosomal patterning of mRNA expression in mouse dorsal striatum, reflecting early developmental expression of . In the ventral striatum, Pnoc expression was was clustered across the nucleus accumbens core and medial shell, including in adult striatum. We found that Pnoc reporter cells largely comprise a population of dopamine receptor D1 ( ) expressing medium spiny projection neurons localized in dorsal striosomes, known to be unique among striatal projections neurons for their direct innervation of midbrain dopamine neurons. These findings provide new understanding of the intersection of the N/OFQ system among basal ganglia circuits with particular implications for developmental regulation or wiring of striatal-nigral circuits.
PubMed: 38798373
DOI: 10.1101/2024.05.15.594426 -
BioRxiv : the Preprint Server For... Apr 2024Opioid use disorder is heritable, yet its genetic etiology is largely unknown. Analysis of addiction model traits in rodents (e.g., opioid behavioral sensitivity and...
Opioid use disorder is heritable, yet its genetic etiology is largely unknown. Analysis of addiction model traits in rodents (e.g., opioid behavioral sensitivity and withdrawal) can facilitate genetic and mechanistic discovery. C57BL/6J and C57BL/6NJ substrains have extremely limited genetic diversity, yet can show reliable phenotypic diversity which together, can facilitate gene discovery. The C57BL/6NJ substrain was less sensitive to oxycodone (OXY)-induced locomotor activity compared to the C57BL/6J substrain. Quantitative trait locus (QTL) mapping in an F2 cross identified a distal chromosome 1 QTL explaining 7-12% of the variance in OXY locomotor sensitivity and anxiety-like withdrawal in the elevated plus maze. We identified a second QTL for withdrawal on chromosome 5 near the candidate gene Gabra2 (alpha-2 subunit of GABA-A receptor) explaining 9% of the variance. Next, we generated recombinant lines from an F2 founder spanning the distal chromosome 1 locus (163-181 Mb), captured the QTL for OXY sensitivity and withdrawal, and fine-mapped a 2.45-Mb region (170.16-172.61 Mb). There were five striatal cis-eQTL transcripts in this region (Pcp4l1, Ncstn, Atp1a2, Kcnj9, Igsf9), two of which were confirmed at the protein level (KCNJ9, ATP1A2). Kcnj9, a.k.a., GIRK3, codes for a potassium channel that is a major effector of mu opioid receptor signaling. Atp1a2 codes for a subunit of a Na+/K+ ATPase enzyme that regulates neuronal excitability and shows adaptations following chronic opioid administration. To summarize, we identified genetic sources of opioid behavioral differences in C57BL/6 substrains, two of the most widely and often interchangeably used substrains in opioid addiction research.
PubMed: 38798314
DOI: 10.1101/2024.04.16.589731 -
Pharmaceuticals (Basel, Switzerland) May 2024Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely utilized pharmaceuticals worldwide. Besides their recognized anti-inflammatory effects, these... (Review)
Review
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely utilized pharmaceuticals worldwide. Besides their recognized anti-inflammatory effects, these drugs exhibit various other pleiotropic effects in several cells, including platelets. Within this article, the multifaceted properties of NSAIDs on platelet functions, activation and viability, as well as their interaction(s) with established antiplatelet medications, by hindering several platelet agonists' pathways and receptors, are thoroughly reviewed. The efficacy and safety of NSAIDs as adjunctive therapies for conditions involving inflammation and platelet activation are also discussed. Emphasis is given to the antiplatelet potential of commonly administered NSAIDs medications, such as ibuprofen, diclofenac, naproxen and ketoprofen, alongside non-opioid analgesic and antipyretic medications like paracetamol. This article delves into their mechanisms of action against different pathways of platelet activation, aggregation and overall platelet functions, highlighting additional health-promoting properties of these anti-inflammatory and analgesic agents, without neglecting the induced by these drugs' side-effects on platelets' functionality and thrombocytopenia. Environmental issues emerging from the ever-increased subscription of these drugs are also discussed, along with the need for novel water treatment methodologies for their appropriate elimination from water and wastewater samples. Despite being efficiently eliminated during wastewater treatment processes on occasion, NSAIDs remain prevalent and are found at significant concentrations in water bodies that receive effluents from wastewater treatment plants (WWTPs), since there is no one-size-fits-all solution for removing all contaminants from wastewater, depending on the specific characteristics of the wastewater. Several novel methods have been studied, with adsorption being proposed as a cost-effective and environmentally friendly method for wastewater purification from such drugs. This article also presents limitations and future prospects regarding the observed antiplatelet effects of NSAIDs, as well as the potential of novel derivatives of these compounds, with benefits in other important platelet functions.
PubMed: 38794197
DOI: 10.3390/ph17050627 -
Journal of Clinical Medicine May 2024In the palliative care population, prescription opioids are often considered viable pain relief options. However, in this complex patient population, the adverse effects... (Review)
Review
In the palliative care population, prescription opioids are often considered viable pain relief options. However, in this complex patient population, the adverse effects of opioid medications should be identified and managed without delay. Common adverse effects can include constipation, nausea, somnolence, dizziness, vomiting, and pruritus. Less common adverse effects can include potentially lethal respiratory depression and cardiovascular effects. Critical aspects of safe opioid prescribing are recognition of side effects and knowledge of effective management strategies; prompt management is necessary for uninterrupted pain relief. Most complications are managed with general approaches such as dose reduction, opioid rotation, alternate routes of administration, and symptomatic management. The only opioid-induced complication for which US Food and Drug Administration-approved treatments currently exist is constipation. Treating laxative-refractory opioid-induced constipation (OIC) with peripherally acting mu-opioid receptor antagonists (PAMORAs), which block gastrointestinal opioid receptors, can restore gastrointestinal motility and fluid secretion. This narrative review discusses key complications of prescription opioid treatment and their management in the palliative care setting.
PubMed: 38792289
DOI: 10.3390/jcm13102746