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.

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.

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.

Selection of DNA-Encoded Libraries to Protein Targets within and on Living Cells.

We report the selection of DNA-encoded small molecule libraries against protein targets within the cytosol and on the surface of live cells. The approach relies on generation of a covalent linkage of the DNA to protein targets by affinity labeling. This cross-linking event enables subsequent copurification by a tag on the recombinant protein.

A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists.

Between 2000 and 2005 several studies revealed that morphine is more potent and exhibits fewer side effects in beta-arrestin 2 knockout mice. These findings spurred efforts to develop opioids that signal primarily via G protein activation and do not, or only very weakly, recruit beta-arrestin. Development of such molecules targeting the mu opioid receptor initially outpaced those targeting the kappa, delta and nociceptin opioid receptors, with the G protein-biased mu opioid agonist oliceridine/TRV130 having completed phase III clinical trials with improved therapeutic window to treat moderate-to-severe acute pain.

Rubiscolins are naturally occurring G protein-biased delta opioid receptor peptides.

The impact that β-arrestin proteins have on G protein-coupled receptor trafficking, signaling and physiological behavior has gained much appreciation over the past decade. A number of studies have attributed the side effects associated with the use of naturally occurring and synthetic opioids, such as respiratory depression and constipation, to excessive recruitment of β-arrestin. These findings have led to the development of biased opioid small molecule agonists that do not recruit β-arrestin, activating only the canonical G protein pathway.

Arrestin recruitment and signaling by G protein-coupled receptor heteromers.

G protein-coupled receptors (GPCR) have a long history of being considered a prime target for drug development to treat a plethora of diseases and disorders. In fact in 1827, the first approved therapeutic in the United States was morphine, a drug that targets a GPCR, namely the mu opioid receptor. However, with the rise in biologics over the last two decades, the market share of small molecules targeting GPCRs has declined.