Discovery of Potent Kappa Opioid Receptor Agonists Derived from Akuammicine.

Akuammicine (), an alkaloid isolated from , is an agonist of the kappa opioid receptor (κOR). To establish structure-activity relationships (SARs) for this structurally unique κOR ligand, a collection of semisynthetic derivatives was synthesized. Evaluating these derivatives for their ability to activate the κOR and mu opioid receptor (μOR) revealed key SAR trends and identified derivatives with enhanced κOR potency.

High-Yield Large-Scale Suspended Graphene Membranes over Closed Cavities for Sensor Applications.

Suspended membranes of monatomic graphene exhibit great potential for applications in electronic and nanoelectromechanical devices. In this work, a "hot and dry" transfer process is demonstrated to address the fabrication and patterning challenges of large-area graphene membranes on top of closed, sealed cavities. Here, "hot" refers to the use of high temperature during transfer, promoting the adhesion.

Identification of 1,3,8-Triazaspiro[4.5]Decane-2,4-Dione Derivatives as a Novel Opioid Receptor-Selective Agonist Chemotype.

opioid receptors (DORs) hold potential as a target for neurologic and psychiatric disorders, yet no DOR agonist has proven efficacious in critical phase II clinical trials. The exact reasons for the failure to produce quality drug candidates for the DOR are unclear. However, it is known that certain DOR agonists can induce seizures and exhibit tachyphylaxis.

ClickArr: a novel, high-throughput assay for evaluating β-arrestin isoform recruitment.

Modern methods for quantifying signaling bias at G protein-coupled receptors (GPCRs) rely on using a single β-arrestin isoform. However, it is increasingly appreciated that the two β-arrestin isoforms have unique roles, requiring the ability to assess β-arrestin isoform preference. Thus, methods are needed to efficiently screen the recruitment of both β-arrestin isoforms as they compete for a target GPCR in cells.

Receptor expression and signaling properties in the brain, and structural ligand motifs that contribute to delta opioid receptor agonist-induced seizures.

The δ opioid receptor (δOR) is a therapeutic target for the treatment of various neurological disorders, such as migraines, chronic pain, alcohol use, and mood disorders. Relative to μ opioid receptor agonists, δOR agonists show lower abuse liability and may be potentially safer analgesic alternatives. However, currently no δOR agonists are approved for clinical use.

Modified Akuamma Alkaloids with Increased Potency at the Mu-opioid Receptor.

Akuammine () and pseudoakuammigine () are indole alkaloids found in the seeds of the akuamma tree (). Both alkaloids are weak agonists of the mu opioid receptor (μOR); however, they produce minimal effects in animal models of antinociception. To probe the interactions of and at the opioid receptors, we have prepared a collection of 22 semisynthetic derivatives.

Copper Modulates Adult Neurogenesis in Brain Subventricular Zone.

The subventricular zone (SVZ) in lateral ventricles is the largest neurogenic region in adult brain containing high amounts of copper (Cu). This study aims to define the role of Cu in adult neurogenesis by chelating labile Cu ions using a well-established Cu chelator D-Penicillamine (D-Pen). A neurosphere model derived from adult mouse SVZ tissues was established and characterized for its functionality with regards to neural stem/progenitor cells (NSPCs).

Exploration of beta-arrestin isoform signaling pathways in delta opioid receptor agonist-induced convulsions.

The δ-opioid receptor (δOR) has been considered as a therapeutic target in multiple neurological and neuropsychiatric disorders particularly as δOR agonists are deemed safer alternatives relative to the more abuse-liable µ-opioid receptor drugs. Clinical development of δOR agonists, however, has been challenging in part due to the seizure-inducing effects of certain δOR agonists. Especially agonists that resemble the δOR-selective agonist SNC80 have well-established convulsive activity.

Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors.

The delta opioid receptor is a Gi-protein-coupled receptor (GPCR) with a broad expression pattern both in the central nervous system and the body. The receptor has been investigated as a potential target for a multitude of significant diseases including migraine, alcohol use disorder, ischemia, and neurodegenerative diseases. Despite multiple attempts, delta opioid receptor-selective molecules have not been translated into the clinic.

Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery II.

A few neurotransmitter systems have fascinated the research community, as muchas the opioid system (i.e., opioid ligands and their receptors) [.

Sex- and β-arrestin-dependent effects of kappa opioid receptor-mediated ethanol consumption.

The kappa opioid receptor is a known regulator of ethanol consumption, but the molecular mechanisms behind its actions have been underexplored. The scaffolding protein β-arrestin 2 has previously been implicated in driving ethanol consumption at the related delta opioid receptor and has also been suggested to be a driver behind other negative kappa opioid receptor mediated effects. Here, we used kappa opioid agonists with different efficacies for recruiting β-arrestin 2 and knockout animals to determine whether there is a role for β-arrestin 2 in the modulation of voluntary ethanol consumption by the kappa opioid receptor.

An updated assessment of the translational promise of G-protein-biased kappa opioid receptor agonists to treat pain and other indications without debilitating adverse effects.

Kappa opioid receptor (κOR) agonists lack the abuse liability and respiratory depression effects of clinically used mu opioid receptor (μOR) analgesics and are hypothesized to be safer alternatives. However, κOR agonists have limiting adverse effects of their own, including aversion, sedation, and mood effects, that have hampered their clinical translation. Studies performed over the last 15 years have suggested that these adverse effects could result from activation of distinct intracellular signaling pathways that are dependent on β-arrestin, whereas signaling downstream of G protein activation produces antinociception.

Identification of a Novel Delta Opioid Receptor Agonist Chemotype with Potential Negative Allosteric Modulator Capabilities.

The δ-opioid receptor (δOR) holds great potential as a therapeutic target. Yet, clinical drug development, which has focused on δOR agonists that mimic the potent and selective tool compound SNC80 have largely failed. It has increasingly become apparent that the SNC80 scaffold carries with it potent and efficacious β-arrestin recruitment.

Modulating β-arrestin 2 recruitment at the δ- and μ-opioid receptors using peptidomimetic ligands.

μ-Opioid receptor agonists provide potent and effective acute analgesia; however, their therapeutic window narrows considerably upon repeated administration, such as required for treating chronic pain. In contrast, bifunctional μ/δ opioid agonists, such as the endogenous enkephalins, have potential for treating both acute and chronic pain. However, enkephalins recruit β-arrestins, which correlate with certain adverse effects at μ- and δ-opioid receptors.

Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder.

extract and kratom alkaloids decrease alcohol consumption in mice at least in part through actions at the δ-opioid receptor (δOR). However, the most potent opioidergic kratom alkaloid, 7-hydroxymitragynine, exhibits rewarding properties and hyperlocomotion presumably due to preferred affinity for the mu opioid receptor (µOR). We hypothesized that opioidergic kratom alkaloids like paynantheine and speciogynine with reduced µOR potency could provide a starting point for developing opioids with an improved therapeutic window to treat alcohol use disorder.

Sensitive capacitive pressure sensors based on graphene membrane arrays.

The high flexibility, impermeability and strength of graphene membranes are key properties that can enable the next generation of nanomechanical sensors. However, for capacitive pressure sensors, the sensitivity offered by a single suspended graphene membrane is too small to compete with commercial sensors. Here, we realize highly sensitive capacitive pressure sensors consisting of arrays of nearly ten thousand small, freestanding double-layer graphene membranes.

A Novel Mitragynine Analog with Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception with Attenuated Adverse Effects.

Mitragynine and 7-hydroxymitragynine (7OH) are the major alkaloids mediating the biological actions of the psychoactive plant kratom. To investigate the structure-activity relationships of mitragynine/7OH templates, we diversified the aromatic ring of the indole at the C9, C10, and C12 positions and investigated their G-protein and arrestin signaling mediated by mu opioid receptors (MOR). Three synthesized lead C9 analogs replacing the 9-OCH group with phenyl (), methyl (), or 3'-furanyl [ ()] substituents demonstrated partial agonism with a lower efficacy than DAMGO or morphine in heterologous G-protein assays and synaptic physiology.

β-Arrestin-dependent ERK signaling reduces anxiety-like and conditioned fear-related behaviors in mice.

G protein-coupled receptors (GPCRs) are implicated in the regulation of fear and anxiety. GPCR signaling involves canonical G protein pathways but can also engage downstream kinases and effectors through scaffolding interactions mediated by β-arrestin. Here, we investigated whether β-arrestin signaling regulates anxiety-like and fear-related behavior in mice in response to activation of the GPCR δ-opioid receptor (δOR or DOR).

Engineering Quick- and Long-acting Naloxone Delivery Systems for Treating Opioid Overdose.

Purpose: Opioids have been the main factor for drug overdose deaths in the United States. Current naloxone delivery systems are effective in mitigating the opioid effects only for hours. Naloxone-loaded poly(lactide-co-glycolide) (PLGA) microparticles were prepared as quick- and long-acting naloxone delivery systems to extend the naloxone effect as an opioid antidote.

A non-convulsant delta-opioid receptor agonist, KNT-127, reduces cortical spreading depression and nitroglycerin-induced allodynia.

Objective: The aim of this study was to determine if the non-convulsant delta-opioid receptor (DOR) agonist, KNT-127, could inhibit migraine-associated endpoints.

Background: The DOR has been identified as a therapeutic target for migraine. However, the development of delta agonists is limited as some ligands have seizurogenic properties, which may be related to their ability to induce receptor internalization.

Isolation and Pharmacological Characterization of Six Opioidergic Alkaloids.

The seeds of the akuamma tree () have been used as a traditional treatment for pain and fever. Previous studies have attributed these effects to a series of indole alkaloids found within the seed extracts; however, these pharmacological studies were significantly limited in scope. Herein, an isolation protocol employing pH-zone-refining countercurrent chromatography was developed to provide six of the akuamma alkaloids in high purity and quantities sufficient for more extensive biological evaluation.

The CUL3/neddylation inhibitor MLN4924 reduces ethanol-induced locomotor sensitization and inflammatory pain allodynia in mice.

Heterologous sensitization of adenylyl cyclase (AC) is defined by an enhanced cAMP response following persistent activation of Gα-coupled receptors. This phenomenon was first observed in cellular models, and later reported in animal models of inflammatory pain or following chronic exposure to drugs of abuse including opioids and cocaine. Recently, we used genome-wide siRNA screening to identify Cullin3 signaling as a mediator of AC sensitization in cellular models.

The Meta-Position of Phe in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors.

As tool compounds to study cardiac ischemia, the endogenous δ-opioid receptors (δOR) agonist Leu-enkephalin and the more metabolically stable synthetic peptide (d-Ala, d-Leu)-enkephalin are frequently employed. However, both peptides have similar pharmacological profiles that restrict detailed investigation of the cellular mechanism of the δOR's protective role during ischemic events. Thus, a need remains for δOR peptides with improved selectivity and unique signaling properties for investigating the specific roles for δOR signaling in cardiac ischemia.

G protein-biased kratom-alkaloids and synthetic carfentanil-amide opioids as potential treatments for alcohol use disorder.

Background And Purpose: Mitragyna speciosa, more commonly known as kratom, is a plant that contains opioidergic alkaloids but is unregulated in most countries. Kratom is used in the self-medication of chronic pain and to reduce illicit and prescription opioid dependence. Kratom may be less dangerous than typical opioids because of the stronger preference of kratom alkaloids to induce receptor interaction with G proteins over β-arrestin proteins.