Revisiting dezocine for opioid use disorder: A narrative review of its potential abuse liability

CNS Neuroscience & Therapeutics, Год журнала: 2024, Номер 30(9)

Опубликована: Сен. 1, 2024

Abstract Aims Opioid use disorder (OUD) remains a serious public health problem. maintenance treatment is effective but under‐utilized, hard to access under existing federal regulations, and, once patients achieve OUD stability, challenging discontinue. Fewer than 2% of persons with stop using opioids completely. There have been calls from advocacy groups, governmental agencies, and officials for new treatments OUD. Dezocine, non‐scheduled opioid previously used in the United States currently widely prescribed China pain management, could be candidate novel medication U.S. Nonetheless, date, there no reviews clinical preclinical literature detailing dezocine's abuse potential, key consideration assessing its utility. Discussion are English language reports human abuse, dependence, or overdose dezocine, despite years extensive use. few case dezocine Chinese literature, deaths. Dezocine perceived as an “liked” by opioid‐experienced non‐human primates, properties that not dose‐dependent mitigated ceiling effects—higher doses do result more “liking.” little withdrawal, spontaneous precipitated, humans, monkeys, rats, mice treated chronically alone. However, at some doses, can precipitate withdrawal humans monkeys dependent on other opioids. In rodents, reduces severity morphine rewarding Conclusions Although reinforcing prior concurrent within restricted dose range, only anecdotal long history humans. Given evidence limited it useful both in‐depth studies would required re‐considered

Язык: Английский

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Ligand-Induced Biased Activation of GPCRs: Recent Advances and New Directions from In Silico Approaches

Molecules, Год журнала: 2025, Номер 30(5), С. 1047 - 1047

Опубликована: Фев. 25, 2025

G-protein coupled receptors (GPCRs) are the largest family of membrane proteins engaged in transducing signals from extracellular environment into cell. GPCR-biased signaling occurs when two different ligands, sharing same binding site, induce distinct pathways. This selective offers significant potential for design safer and more effective drugs. Although its molecular mechanism remains elusive, big efforts made to try explain this using a wide range methods. Recent advances computational techniques AI technology have introduced variety simulations machine learning tools that facilitate modeling GPCR signal transmission analysis ligand-induced biased signaling. In review, we present current state silico approaches elucidate structural includes dynamics capture main interactions causing bias. We also highlight major contributions impacts transmembrane domains, loops, mutations mediating Moreover, discuss impact models on bias prediction diffusion-based generative ligands. Ultimately, review addresses future directions studying problem through approaches.

Язык: Английский

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Principles and Design of Molecular Tools for Sensing and Perturbing Cell Surface Receptor Activity

Chemical Reviews, Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

Cell-surface receptors are vital for controlling numerous cellular processes with their dysregulation being linked to disease states. Therefore, it is necessary develop tools study and the signaling pathways they control. This Review broadly describes molecular approaches that enable 1) visualization of determine localization distribution; 2) sensing receptor activation permanent readouts as well in real time; 3) perturbing activity mimicking receptor-controlled learn more about these processes. Together, have provided valuable insight into fundamental biology helped characterize therapeutics target receptors.

Язык: Английский

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Dezocine and Addiction: Friend or Foe?

Pharmaceuticals, Год журнала: 2025, Номер 18(3), С. 386 - 386

Опубликована: Март 8, 2025

The neurological effects of opium were first described over 8000 years ago. Morphine was isolated in 1803 and by the mid-1800s had become both a pain-relieving blessing an addictive curse. As part crusade to identify safer more reliable alternatives morphine, dezocine (Dalgan®) marketed US 1986. Its use discontinued 2011 without revealing reasons, but it remains one most widely used analgesic agents China today. Dezocine’s unique pharmacology makes effective with limited opioid-associated side little or no reported potential for dependence addiction. In addition, dezocine’s blocking effect on serotonin norepinephrine transporters recommends its further exploration as treatment various chronic neuropathic pain conditions. Most recently, data suggest that might represent viable addiction management. This report focuses supporting non-addictive profile treat opioid withdrawal, well recent efforts generate formulations support sub-chronic dosing.

Язык: Английский

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Biased Signaling in G Protein-Coupled Receptors: Understanding the Biological Relevance and Tools for Probing Functionally Selective Ligands

Biochemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 18, 2025

Biased signaling has transformed pharmacology by revealing that receptors, particularly G protein-coupled receptors (GPCRs), can activate specific intracellular pathways selectively rather than uniformly. This discovery enables the development of targeted therapeutics minimize side effects precisely modulating receptor activity. Functionally selective ligands, which preferentially distinct branches, have become essential tools for exploring mechanisms and uncovering complexities GPCR signaling. These ligands help clarify function in various physiological pathological contexts, offering profound implications therapeutic innovation. GPCRs, mediate a wide range cellular responses through coupling to proteins arrestins, are key pharmacological targets, with nearly third FDA-approved drugs acting on them. Recent advancements biosensor development, multiplex assay platforms, deep mutational scanning methods improving our ability define signaling, allowing better understanding biased pathways.

Язык: Английский

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The Hunt for the Putative Epoxyeicosatrienoic Acid Receptor

ACS Chemical Biology, Год журнала: 2025, Номер unknown

Опубликована: Март 24, 2025

Epoxyeicosatrienoic acids, or EETs, are signaling molecules formed by the metabolism of arachidonic acid cytochrome P450 enzymes. They well-known for their anti-inflammatory effects, ability to lower blood pressure, and benefits cardiovascular outcomes. Despite wealth data demonstrating physiological benefits, putative high-affinity receptor that mediates these effects is yet be identified. The recent report sphingosine-1-phosphate 1 (S1PR1) a related epoxy lipid prompted us ask, "Why has EET not been discovered yet? What information about discoveries epoxide receptors can help identify receptor?" In this review, we summarize evidence supporting exists. We then review showing EETs binding other, low-affinity discovery similar metabolites serve as model identifying receptor. hope will revitalize search important receptor, which facilitate development therapeutics.

Язык: Английский

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Structure–Signal Relationships of the <i>δ</i>-Opioid-Receptor (DOR)-Selective Agonist KNT-127—Part I: Impact of the Morphinan Skeleton on the G-Protein-Biased DOR Agonism

Chemical and Pharmaceutical Bulletin, Год журнала: 2025, Номер 73(3), С. 246 - 256

Опубликована: Март 28, 2025

The δ-opioid receptor (DOR) is a promising target for developing novel analgesics due to its lower risk of causing side effects compared the μ-opioid (MOR), which commonly associated with dependence, respiratory depression, and other adverse effects. KNT-127, DOR-selective agonist morphinan skeleton, offers analgesic antidepressant benefits without inducing convulsions at therapeutic doses, unlike conventional DOR SNC80. While previous studies have suggested that KNT-127 exhibits reduced β-arrestin recruitment, signaling pathway implicated in opioid effects, ligand structural basis this biased remains unclear. In study, we explored structure-signal relationships focusing on quinoline moiety, known serve as an address domain responsible selectivity. Modifying moiety by removing aromatic rings selectivity potency relation G-protein activation while diminishing both efficacy recruitment. These results suggest skeleton critical differentially modulates Together, our study expands message-address concept, previously limited selectivity, providing insights into G-protein-biased agonism agonists, thereby guiding design safer DOR-targeting therapeutics.

Язык: Английский

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Opioid Analgesics: Rise and Fall of Ligand Biased Signaling and Future Perspectives in the Quest for the Holy Grail

CNS Drugs, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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Mas Receptor as a Target for Neuropathic Pain Management: Insights into Angiotensin-(1-7) Signaling and Therapeutic Opportunities

Journal for Research in Applied Sciences and Biotechnology, Год журнала: 2025, Номер 4(2), С. 167 - 176

Опубликована: Апрель 30, 2025

Mas is a G protein-coupled receptor (GPCR) that binds to Angiotensin (1-7) and it evaluated as an important element of non classical Renin System. While the RAS axis has been considered pro-inflammatory pro-nociceptive by leveraging II AT1 receptor, /Mas offers anti-inflammatory, vessels dilating, neuroprotective functions. It produced two mechanisms first, obtained from via mechanism angiotensin converting enzyme 2 (ACE2) also binding formed Ang-(1-7) its activates several signaling pathways such PI3K/Akt, ERK1/2 nitric oxide (NO). These together prevent neuronal death, decrease oxidative stress inhibit nuclear factor-kappa B (NF-κB), reduces expression various cytokines like TNF-α, IL-1β IL-6. With regard neuropathic pain, contributes regulation glial-neuronal crosstalk negative microglial astrocytic activity neuroimmune balance. Experimental studies have shown use or synthetic activators attenuates mechanical alodynia thermal hypoesthesia, proving Marques colleagues’ hypothesis possible therapeutic applications. Also, functional cross-talk with other pain-modulatory systems, including endogenous opioid endocannabinoid contributing enhancer this sort analgesia. Thus, novel (1-7)/Mas pathway can be promising candidate for new non-opioid analgesic treatment pain. Further research in agonists, peptide analogs, targeted drug delivery system shows there potential practical application these discoveries.

Язык: Английский

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The many facets of biased signaling: Mechanisms and possible therapeutic implications

Pharmacology & Therapeutics, Год журнала: 2025, Номер unknown, С. 108877 - 108877

Опубликована: Май 1, 2025

Язык: Английский

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