Editorial: Therapeutic potential of the cannabinoid CB2 receptor DOI Creative Commons

Reem Smoum,

Uwe Grether, Meliha Karsak

и другие.

Frontiers in Pharmacology, Год журнала: 2022, Номер 13

Опубликована: Окт. 7, 2022

EDITORIAL article Front. Pharmacol., 07 October 2022Sec. Experimental Pharmacology and Drug Discovery Volume 13 - 2022 | https://doi.org/10.3389/fphar.2022.1039564

Язык: Английский

Structural basis of selective cannabinoid CB2 receptor activation DOI Creative Commons
Xiaoting Li,

Hao Chang,

Jara Bouma

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Март 15, 2023

Abstract Cannabinoid CB 2 receptor (CB R) agonists are investigated as therapeutic agents in the clinic. However, their molecular mode-of-action is not fully understood. Here, we report discovery of LEI-102, a R agonist, used conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate selective activation by binding kinetics, site-directed mutagenesis, cryo-EM studies. We identify key residues for activation. Highly lipophilic HU308 endocannabinoids, but more polar APD371, CP55,940, reach pocket through membrane channel TM1-TM7. Favorable physico-chemical properties LEI-102 enable oral efficacy chemotherapy-induced nephropathy model. This study delineates mechanism highlights role lipophilicity engagement. may have implications GPCR drug design sheds light on endogenous ligands.

Язык: Английский

Процитировано

48

CB2 receptor in the CNS: From immune and neuronal modulation to behavior DOI Creative Commons
Wanda Grabon, Sylvain Rheims, Jonathon Smith

и другие.

Neuroscience & Biobehavioral Reviews, Год журнала: 2023, Номер 150, С. 105226 - 105226

Опубликована: Май 8, 2023

Язык: Английский

Процитировано

29

Flipping the GPCR Switch: Structure-Based Development of Selective Cannabinoid Receptor 2 Inverse Agonists DOI Creative Commons
Miroslav Kosar, Roman C. Sarott, David A. Sykes

и другие.

ACS Central Science, Год журнала: 2024, Номер 10(5), С. 956 - 968

Опубликована: Март 11, 2024

We report a blueprint for the rational design of G protein coupled receptor (GPCR) ligands with tailored functional response. The present study discloses structure-based cannabinoid type 2 (CB2R) selective inverse agonists (S)-1 and (R)-1, which were derived from privileged agonist HU-308 by introduction phenyl group at gem-dimethylheptyl side chain. Epimer (R)-1 exhibits high affinity CB2R Kd = 39.1 nM serves as platform synthesis wide variety probes. Notably, first time these fluorescent probes retain their functionality, affinity, selectivity independent linker fluorophore substitution. Ligands (S)-1, derivatives act in CB2R-mediated cAMP well recruitment assays do not trigger β-arrestin-receptor association. Furthermore, no activation was detected live cell ERK1/2 phosphorylation Ca2+-release assays. Confocal fluorescence imaging experiments (R)-7 (Alexa488) (R)-9 (Alexa647) employing BV-2 microglial cells visualized expressed endogenous levels. Finally, molecular dynamics simulations corroborate initial docking data restrict movement toggle switch Trp2586.48 thereby stabilize its inactive state.

Язык: Английский

Процитировано

9

The intervention of cannabinoid receptor in chronic and acute kidney disease animal models: a systematic review and meta-analysis DOI Creative Commons
Zihao Zhao,

Qianqian Yan,

Junwei Xie

и другие.

Diabetology & Metabolic Syndrome, Год журнала: 2024, Номер 16(1)

Опубликована: Фев. 15, 2024

Cannabinoid receptors are components of the endocannabinoid system that affect various physiological functions. We aim to investigate effect cannabinoid receptor modulation on kidney disease. PubMed, Web Science databases, and EMBASE were searched. Articles selection, data extraction quality assessment independently performed by two investigators. The SYRCLE's RoB tool was used assess risk study bias, pooled SMD using a random-effect model 95% CIs calculated. Subgroup analyses conducted in preselected subgroups, publication bias evaluated. compared effects CB1 CB2 antagonists and/or knockout agonists genetic regulation renal function, blood glucose levels, body weight, pathological damage-related indicators different models chronic acute injury. blockade or could significantly reduce urea nitrogen [SMD,- 1.67 (95% CI - 2.27 1.07)], serum creatinine [SMD, 1.88 2.91 0.85)], albuminuria 1.60 2.16 1.04)] dysfunction animals with control group. activation group 0.97 1.83 0.11)] 2.43 4.63 0.23)] results suggest targeting receptors, particularly agonists, can improve function inflammatory responses, exerting protective maintaining therapeutic potential types

Язык: Английский

Процитировано

7

DeLA-DrugSelf: Empowering multi-objective de novo design through SELFIES molecular representation DOI Creative Commons
Domenico Alberga, G. Lamanna, Giovanni Graziano

и другие.

Computers in Biology and Medicine, Год журнала: 2024, Номер 175, С. 108486 - 108486

Опубликована: Апрель 16, 2024

In this paper, we introduce DeLA-DrugSelf, an upgraded version of DeLA-Drug [J. Chem. Inf. Model. 62 (2022) 1411-1424], which incorporates essential advancements for automated multi-objective de novo design. Unlike its predecessor, relies on SMILES notation molecular representation, DeLA-DrugSelf employs a novel and robust representation string named SELFIES (SELF-referencing embedded string). The generation process in not only involves substitutions to the initial representing starting query molecule but also insertions deletions. This enhancement makes significantly more adept at executing data-driven scaffold decoration lead optimization strategies. Remarkably, explicitly addresses SELFIES-related collapse issue, considering collapse-free compounds during generation. These undergo rigorous quality metrics evaluation, highlighting substantial terms drug-likeness, uniqueness, novelty compared molecules generated by previous algorithm. To evaluate potential as mutational operator within genetic algorithm framework optimization, employed fitness function based Pareto dominance. Our objectives focused target-oriented properties aimed optimizing known cannabinoid receptor 2 (CB2R) ligands. results obtained indicate that available user-friendly web platform (https://www.ba.ic.cnr.it/softwareic/delaself/), can effectively contribute bioactive user-defined parameters.

Язык: Английский

Процитировано

7

Potential of CBD Acting on Cannabinoid Receptors CB1 and CB2 in Ischemic Stroke DOI Open Access
Iu Raïch, Jaume Lillo, Rafael Rivas‐Santisteban

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(12), С. 6708 - 6708

Опубликована: Июнь 18, 2024

Stroke is one of the leading causes death. It not only affects adult people but also many children. estimated that, every year, 15 million suffer a stroke worldwide. Among them, 5 die, while are left permanently disabled. In this sense, research to find new treatments should be accompanied with therapies combat neuronal death and avoid developing cognitive impairment dementia. Phytocannabinoids among compounds that have been used by mankind for longest period history. Their beneficial effects such as pain regulation or neuroprotection widely known make them possible therapeutic agents high potential. These bind cannabinoid receptors CB

Язык: Английский

Процитировано

6

Distinct activation mechanisms regulate subtype selectivity of Cannabinoid receptors DOI Creative Commons
Soumajit Dutta, Diwakar Shukla

Communications Biology, Год журнала: 2023, Номер 6(1)

Опубликована: Май 5, 2023

Abstract Design of cannabinergic subtype selective ligands is challenging because high sequence and structural similarities cannabinoid receptors (CB 1 CB 2 ). We hypothesize that the selectivity designed can be explained by ligand binding to conformationally distinct states between receptors. Analysis ~ 700 μ s unbiased simulations using Markov state models VAMPnets identifies distinctions activation mechanism both Structural dynamic comparisons metastable intermediate allow us observe distinction in pocket volume change during activation. Docking analysis reveals only a few show affinity towards agonists. In contrast, all similar for these These results mechanistically explain agonists deciphering

Язык: Английский

Процитировано

13

Enantiomeric Agonists of the Type 2 Cannabinoid Receptor Reduce Retinal Damage during Proliferative Vitreoretinopathy and Inhibit Hyperactive Microglia In Vitro DOI Creative Commons
A. P. Young,

Anna-Maria Szczesniak,

Karolynn Hsu

и другие.

ACS Pharmacology & Translational Science, Год журнала: 2024, Номер 7(5), С. 1348 - 1363

Опубликована: Апрель 25, 2024

Microglia are resident immune cells of the central nervous system (CNS) and propagate inflammation following damage to CNS, including retina. Proliferative vitreoretinopathy (PVR) is a condition that can emerge retinal detachment characterized by severe microglial proliferation. The type 2 cannabinoid receptor (CB2) an emerging pharmacological target suppress microglial-mediated when eyes or brain damaged. CB2-knockout mice have exacerbated pathology during experimental PVR. We aimed assess anti-inflammatory effects CB2 stimulation in context also explore mechanistic roles microglia function. To CB2, we used highly selective agonist, HU-308, as well its enantiomer, HU-433, which putative agonist. First, β-arrestin2 Gαi recruitment was measured compare activation human vitro heterologous expression system. Both agonists were then utilized mouse model PVR, on damage, inflammation, cell death assessed. Finally, determine HU-308 HU-433 phagocytosis, cytokine release, migration, intracellular signaling. observed more strongly recruited both compared HU-433. Stimulation with either drug effectively blunted LPS- IFNγ-mediated signaling NO TNF release from microglia. Furthermore, drugs reduced IL-6 accumulation, total caspase-3 cleavage, induction Ultimately, this work supports valuable for associated infection sterile retinopathy, although magnitude effector may not be predictive capacity.

Язык: Английский

Процитировано

4

Targeting the endocannabinoid system: Structural determinants and molecular mechanism of allosteric modulation DOI Creative Commons
Jiayi Yuan, Bo Ram Yang, Guanyu Hou

и другие.

Drug Discovery Today, Год журнала: 2023, Номер 28(7), С. 103615 - 103615

Опубликована: Май 11, 2023

Язык: Английский

Процитировано

9

Cannabinoid CB2 receptor orthologues; in vitro function and perspectives for preclinical to clinical translation DOI Creative Commons
Emma R. Carruthers, Natasha L. Grimsey

British Journal of Pharmacology, Год журнала: 2023, Номер 181(14), С. 2247 - 2269

Опубликована: Июнь 24, 2023

Cannabinoid CB

Язык: Английский

Процитировано

9