The role of RGS12 in tissue repair and human diseases DOI Creative Commons

Min Jiang,

Hong-Mei Li,

Qiong Zhang

и другие.

Genes & Diseases, Год журнала: 2024, Номер 12(4), С. 101480 - 101480

Опубликована: Дек. 4, 2024

Regulator of G protein signaling 12 (RGS12) belongs to the superfamily RGS proteins defined by a conserved domain that canonically binds and deactivates heterotrimeric G-proteins. As largest family member, RGS12 is widely expressed in many cells tissues. In past few decades, it has been found affects activity various human body, participates physiological pathological processes, plays an important role pathogenesis diseases. Here, we set out comprehensively review diseases its mechanisms, highlighting possibility as therapeutic target for treatment

Язык: Английский

A cryptic pocket in CB1 drives peripheral and functional selectivity DOI
Vipin Ashok Rangari, Evan S. O’Brien,

Alexander S. Powers

и другие.

Nature, Год журнала: 2025, Номер unknown

Опубликована: Март 5, 2025

Язык: Английский

Процитировано

3

Signaling Modulation Mediated by Ligand Water Interactions with the Sodium Site at μOR DOI Creative Commons
Rohini S. Ople, Nokomis Ramos‐Gonzalez, Qiongyu Li

и другие.

ACS Central Science, Год журнала: 2024, Номер 10(8), С. 1490 - 1503

Опубликована: Июль 17, 2024

The mu opioid receptor (μOR) is a target for clinically used analgesics. However, adverse effects, such as respiratory depression and physical dependence, necessitate the development of alternative treatments. Recently we reported novel strategy to design functionally selective opioids by targeting sodium binding allosteric site in μOR with supraspinally active analgesic named C6guano. Presently, improve systemic activity this ligand, structure-based design, identifying new ligand RO76 where flexible alkyl linker polar guanidine guano group swapped benzyl alcohol, targeted indirectly through waters. A cryoEM structure bound μOR-Gi complex confirmed that interacts residues water molecule, unlike C6guano which engages directly. Signaling assays coupled APEX based proximity labeling show pocket modulates efficacy trafficking. In mice, was systemically tail withdrawal showed reduced liabilities compared those morphine. summary, molecules may be an avenue modulate signaling properties opioids, potentially extended other G-protein receptors conserved.

Язык: Английский

Процитировано

5

Ketamine and Major Ketamine Metabolites Function as Allosteric Modulators of Opioid Receptors DOI
Ivone Gomes, Achla Gupta, Elyssa B. Margolis

и другие.

Molecular Pharmacology, Год журнала: 2024, Номер 106(5), С. 240 - 252

Опубликована: Авг. 26, 2024

Ketamine is a glutamate receptor antagonist that was developed over 50 years ago as an anesthetic agent. At subanesthetic doses, ketamine and some metabolites are analgesics fast-acting antidepressants, presumably through targets other than receptors. We tested its for activity allosteric modulators of opioid receptors expressed recombinant in heterologous systems with native rodent brain; signaling examined by measuring GTP binding,

Язык: Английский

Процитировано

5

Advances in the structural understanding of opioid allostery DOI Creative Commons
Nokomis Ramos‐Gonzalez, Balázs Varga, Susruta Majumdar

и другие.

Trends in Pharmacological Sciences, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Activation of the μ opioid receptor (MOR) can give analgesia, but also has dangerous side effects. Drugs that target MOR through an allosteric site, meaning they bind outside usual pocket, present a novel mode activation with different pharmacology relative to orthosteric drugs. Recent structural studies valuable new information on how modulators interact MOR.

Язык: Английский

Процитировано

0

Biased agonism in peptide-GPCRs: A structural perspective DOI Creative Commons
Tharindunee Jayakody,

Dinath Kavishka Budagoda,

Krishan Mendis

и другие.

Pharmacology & Therapeutics, Год журнала: 2025, Номер unknown, С. 108806 - 108806

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0

Research Progress in the Synthesis of α-Tertiary Amines via Radical Strategies DOI

Jia‐Heng Fang,

Run Tian,

Ji‐Jun Chen

и другие.

Chinese Journal of Organic Chemistry, Год журнала: 2025, Номер 45(1), С. 22 - 22

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0

Structure-guided design of partial agonists at an opioid receptor DOI Creative Commons
Balázs Varga, Sarah M. Bernhard,

Amal El Daibani

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 13, 2025

Chronic pain and opioid overdose deaths highlight the need for non-addictive analgesics with novel mechanisms. The δ receptor (δOR) is a promising target, as it lacks respiratory depression associated µ (µOR) agonists. However, early δOR full agonists caused seizures, limiting their clinical use. Partial may offer more controlled activation than agonists, but development has been hindered by uncertainty regarding molecular mechanism of partial agonism. Here we show that C6-Quino, bitopic ligand developed through structure-based design, acts selective agonist. Functional studies reveal C6-Quino shows differential activity at G-protein arrestin pathways interacts sodium binding pocket, confirmed cryo-EM analysis. demonstrates oral activity, analgesic in chronic models without causing δOR-related seizures µOR-related adverse effects which have limited usage recent times. This discovery outlines new strategy developing δOR-targeted provides framework optimizing signaling profiles other Class A GPCRs. δ-Opioid receptors are targets management reduced side effects. Here, authors use approach to design characterize agonist, highlighting its potential therapeutic relevance.

Язык: Английский

Процитировано

0

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 DOI Open Access

Keita Kajino,

Tomoya Sugai,

Ryoji Kise

и другие.

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

Процитировано

0

Revisiting dezocine for opioid use disorder: A narrative review of its potential abuse liability DOI Creative Commons
Gordon A. Barr, Heath D. Schmidt, Ashish P. Thakrar

и другие.

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

Процитировано

3

Exploring biased activation characteristics by molecular dynamics simulation and machine learning for the μ-opioid receptor DOI
Jianfang Chen,

Qiaoling Gou,

Xin Chen

и другие.

Physical Chemistry Chemical Physics, Год журнала: 2024, Номер 26(14), С. 10698 - 10710

Опубликована: Янв. 1, 2024

Using aMD simulations with an interpretable deep learning model, the biased activation of μOR two distinct agonists is revealed.

Язык: Английский

Процитировано

2