Developing the Cannabinoid Receptor 2 (CB2) pharmacopoeia: past, present, and future

Whiting, Zak M.; Yin, Jiazhen; Harpe, Sara M. de la; Vernall, Andrea J.; Grimsey, Natasha L.

doi:10.1016/j.tips.2022.06.010

Cited by 32 publications

(45 citation statements)

References 87 publications

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“…A number of CB 2 selective agonists have entered clinical trial phase. 34,35 However, none of these molecules has been approved as a drug by FDA. There are two of the major drawbacks in developing CB 2 selective drugs.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, selective CB 2 selective agonists could be an important drug target for pain and inflammation without the psychoactive side effects caused by the binding to CB 1 . [33][34][35] Lack of subtype selectivity is also a major issue in drug design for other subfamilies of class A GPCRs. For example, the main targets of ergotamine are 5-HT 1B and 5-HT 1D receptors; however, its usage is very limited due to off-target actions on the other 5-HT subtype receptors, particularly on the 5-HT 2B receptor that causes life-threatening cardiovascular disorders.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, selective CB 2 selective agonists could be an important drug target for pain and inflammation without the psychoactive side effects caused by the binding to CB 1 . 33–35…”

Section: Introductionmentioning

confidence: 99%

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Distinct Activation Mechanisms Regulate Subtype Selectivity of Cannabinoid Receptors

Dutta

Shukla

2022

Preprint

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Cannabinoid receptors (CB1 and CB2) are important drug targets for inflammation, obesity, and other central nervous system disorders. However, due to sequence and structural similarities of the ligand binding pockets of these receptors, most of the ligands lack subtype selectivity and cause off-target side effects. CB2 selective agonists can potentially treat pain and inflammation without the psychoactive effects of CB1 agonism. We hypothesize that the subtype selectivity of designed selective ligands can be explained by ligand binding to the conformationally distinct states between CB1 and CB2. To find these conformationally distinct states, we perform 700 μs of unbiased simulations to study the activation mechanism of both the receptors in absence of ligands. The simulation datasets of two receptors were analyzed using Markov state models to identify similarities and distinctions of the major conformational changes associated with activation and allosteric communication between them. Specifically, toggle switch residue movement and its effect on receptor activation differ greatly between CB1 and CB2. Upon further analysis, we discretize the conformational ensembles of both receptors into metastable states using the neural network-based VAMPnets. Structural and dynamic comparisons of these metastable states allow us to decipher a coarse-grained view of protein activation by revealing sequential conversion between these states. Specifically, we observe the difference in the binding pocket volume of different metastable states of CB1, whereas there are minimal changes observed in the CB2. Docking analysis reveals that differential binding pocket volume leads to distinct binding poses and docking affinities of CB2 selective agonists in CB1. Only a few of the intermediate metastable states of CB1 shows high affinity towards CB2 selective agonists. On the other hand, all the CB2 metastable states show a similar affinity for CB2 selective agonists, explaining these ligands overall higher affinity towards CB2. Overall, this computational study mechanistically explains the subtype selectivity of CB2 selective ligands by deciphering the activation mechanism of cannabinoid receptors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Distinct Activation Mechanisms Regulate Subtype Selectivity of Cannabinoid Receptors

Dutta

Shukla

2022

Preprint

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“…The created pharmacophores were validated using a test set of 20 compounds with K i values <100 nM toward human CB2 according to previously reported in vitro studies (Table S1) and a Schrödinger decoy set of 1000 drug-like compounds (average molecular weight (MW) = 400 g/mol) . Active compounds were not discriminated for their intrinsic activities, based on the insights of Markt et al and Brogi et al and because of the inability to adequately represent the Trp258 toggle switch , in pharmacophores. Structures of the 20 active test compounds were downloaded from PubChem .…”

Section: Methodsmentioning

confidence: 99%

Identification of Novel CB2 Ligands through Virtual Screening and In Vitro Evaluation

Stasiulewicz

Leśniak

Bujalska‐Zadrożny

et al. 2023

J. Chem. Inf. Model.

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Cannabinoid receptor type 2 (CB2) is a very promising therapeutic target for a variety of potential indications. However, despite the existence of multiple high affinity CB2 ligands, none have yet been approved as a drug. Therefore, it would be beneficial to explore new chemotypes of CB2 ligands. The recent elucidation of CB2 tertiary structure allows for rational hit identification with structure-based (SB) methods. In this study, we established a virtual screening workflow based on SB techniques augmented with ligand-based ones, including molecular docking, MM–GBSA binding energy calculations, pharmacophore screening, and QSAR. We screened nearly 7 million drug-like, commercially available compounds. We selected 16 molecules for in vitro evaluation and identified two novel, selective CB2 antagonists with K i values of 65 and 210 nM. Both compounds are structurally diverse from CB2 ligands known to date. The established virtual screening protocol may prove useful for hit identification for CB2 and similar molecular targets. The two novel CB2 ligands provide a desired starting point for future optimization and development of potential drugs.

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“…Under normal conditions, CB2R is primarily expressed in the immune system, but there is emerging evidence that various states of disease can lead to robust induction of this receptor. This suggests that CB2R is a viable therapeutic target and for this reason, molecules interacting with CB2R have been tested as potential treatments in a wide array of chronic conditions, including cardiovascular and gastrointestinal/inflammatory bowel disease; liver, kidney, lung, neuro-degenerative and psychiatric disorders; reproductive system and skin pathologies; inflammation; pain; cancer; and osteoporosis (Whiting et al, 2022). Through the years, researchers have designed and synthesized novel ligands targeting CB2R with a preference to be highly selective over the cannabinoid receptor type 1 (CB1R) to avoid undesirable CB1dependent psychotropic effects.…”

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confidence: 99%

Editorial: Therapeutic potential of the cannabinoid CB2 receptor

Smoum

Grether²,

Karsak³

et al. 2022

Front. Pharmacol.

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Editorial on the Research Topic Therapeutic potential of the cannabinoid CB2 receptorThe cannabinoid receptor type 2 (CB2R) has emerged as a promising therapeutic target for treating various pathologies. Under normal conditions, CB2R is primarily expressed in the immune system, but there is emerging evidence that various states of disease can lead to robust induction of this receptor. This suggests that CB2R is a viable therapeutic target and for this reason, molecules interacting with CB2R have been tested as potential treatments in a wide array of chronic conditions, including cardiovascular and gastrointestinal/inflammatory bowel disease; liver, kidney, lung, neuro-degenerative and psychiatric disorders; reproductive system and skin pathologies; inflammation; pain; cancer; and osteoporosis (Whiting et al., 2022). Through the years, researchers have designed and synthesized novel ligands targeting CB2R with a preference to be highly selective over the cannabinoid receptor type 1 (CB1R) to avoid undesirable CB1dependent psychotropic effects. However, the clinical results using these CB2R ligands have been largely ineffective (Morales et al., 2016;An et al., 2020).Greater knowledge of ligand-target binding kinetics, CB2R biased signaling and allosterism, and additional structures of antagonist-and agonist bound CB2R will likely enable more selective drug design (Soethoudt et al., 2017). This will bring new hope for the therapeutic potential of CB2R and a better understanding of the endocannabinoid system (ECS).This Research Topic provides more insight into our current understanding of the CB2R field and its therapeutic potential and highlights new findings.Four comprehensive reviews cover diverse aspects of the therapeutic potential of CB2R. Hashiesh et al. provide a full overview of the pharmacological properties, molecular

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Developing the Cannabinoid Receptor 2 (CB2) pharmacopoeia: past, present, and future

Cited by 32 publications

References 87 publications

Distinct Activation Mechanisms Regulate Subtype Selectivity of Cannabinoid Receptors

Distinct Activation Mechanisms Regulate Subtype Selectivity of Cannabinoid Receptors

Identification of Novel CB2 Ligands through Virtual Screening and In Vitro Evaluation

Editorial: Therapeutic potential of the cannabinoid CB2 receptor

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