Medicinal Chemistry approach, pharmacology and neuroprotective benefits of CB2R modulators in neurodegenerative diseases

Ferrisi, Rebecca; Ceni, Costanza; Bertini, Simone; Macchia, Marco; Manera, Clementina; Gado, Francesca

doi:10.1016/j.phrs.2021.105607

Cited by 15 publications

(15 citation statements)

References 168 publications

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“…Notably, activation of CB 2 Rs results in inhibition of neuroinflammatory signaling pathways ( Bie et al, 2018 ); therefore, this receptor type may be a clinically promising target for the control of brain damage in neurodegenerative disorders, including neuropathic pain, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis ( Benito et al, 2003 ; Benito et al, 2005 ; Han et al, 2013 ; Chung et al, 2016 ; Xu et al, 2016 ; Ferrisi et al, 2021 ). However, to date only a few synthetic CB 2 R agonists have reached an advanced stage of clinical trials (from ClinicalTrials.gov: GW842166X, S-777469, and JTE-907), probably because of the predominance of CB 2 Rs on immune cells, whose activation might cause immunosuppression ( Oláh et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of novel orthosteric-allosteric ligands of the cannabinoid receptor type 2 (CB2R)

et al. 2022

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It is well known that G protein–coupled receptors (GPCRs) assume multiple active states. Orthosteric ligands and/or allosteric modulators can preferentially stabilize specific conformations, giving rise to pathway-biased signaling. One of the most promising strategies to expand the repertoire of signaling-selective GPCR activators consists of dualsteric agents, which are hybrid compounds consisting of orthosteric and allosteric pharmacophoric units. This approach proved to be very promising showing several advantages over monovalent targeting strategies, including an increased affinity or selectivity, a bias in signaling pathway activation, reduced off-target activity and therapeutic resistance. Our study focused on the cannabinoid receptor type 2 (CB2R), considered a clinically promising target for the control of brain damage in neurodegenerative disorders. Indeed, CB2R was found highly expressed in microglial cells, astrocytes, and even in some neuron subpopulations. Here, we describe the design, synthesis, and biological evaluation of two new classes of potential dualsteric (bitopic) CB2R ligands. The new compounds were obtained by connecting, through different linkers, the pharmacophoric portion of the CB2R positive allosteric modulator (PAM), EC21a, with that of the CB2R selective orthosteric agonist LV62, both developed in our laboratories. A preliminary screening enabled us to identify compound JR64a as the most promising of the series. Indeed, functional examination highlighted a signaling ‘bias’ in favor of G protein activation over βarrestin2 recruitment, combined with high affinity for CB2R and the ability to efficiently prevent inflammation in human microglial cells (HMC3) exposed to LPS/TNFα stimulation, thus demonstrating great promise for the treatment of neurodegenerative diseases.

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Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of novel orthosteric-allosteric ligands of the cannabinoid receptor type 2 (CB2R)

et al. 2022

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“…In conclusion, in addition to the above mentioned cannabinoid receptors, other cannabinoid receptors exist in the basal ganglia, such as GPR18, GPR119, and PPARs ( Ferrisi et al, 2021 ), which together constitute the cannabinoid system in the basal ganglia, but the roles of these receptors have not been clarified. Therefore, it is necessary to explore the functions of these cannabinoid receptors in order to refine the mechanism of action of the cannabinoid system.…”

Section: Effects Of Other Cannabinoid Receptors On Parkinson’s Diseasementioning

confidence: 99%

Roles of the Cannabinoid System in the Basal Ganglia in Parkinson’s Disease

Wang

Liu

2022

Front. Cell. Neurosci.

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Parkinson’s disease (PD) is a neurodegenerative disease usually caused by neuroinflammation, oxidative stress and other etiologies. Recent studies have found that the cannabinoid system present in the basal ganglia has a strong influence on the progression of PD. Altering the cannabinoid receptor activation status by modulating endogenous cannabinoid (eCB) levels can exert an anti-movement disorder effect. Therefore, the development of drugs that modulate the endocannabinoid system may be a novel strategy for the treatment of PD. However, eCB regulation is complex, with diverse cannabinoid receptor functions and the presence of dopaminergic, glutamatergic, and γ-aminobutyric signals interacting with cannabinoid signaling in the basal ganglia region. Therefore, the study of eCB is challenging. Here, we have described the function of the cannabinoid system in the basal ganglia and its association with PD in three parts (eCBs, cannabinoid receptors, and factors regulating the cannabinoid metabolism) and summarized the mechanisms of action related to the cannabinoid analogs currently aimed at treating PD. The shortcomings identified from previous studies and the directions that should be explored in the future will provide insights into new approaches and ideas for the future development of cannabinoid-based drugs and the treatment of PD.

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“…Genetic studies have revealed that CB2 receptors knockout (KO) mice showed enhanced microglial activation, neural pathology, and inflammation [ 2 ]. Two different human CB2 receptor isoforms (hCB2A and hCB2B) have been identified [ 33 , 34 ]. hCB2B was mostly observed in the spleen and leukocytes, whereas hCB2A expression was mainly detected in the testis and brain [ 33 , 34 ].…”

Section: The Cannabinoid Type 2 (Cb2) Receptors In Pdmentioning

confidence: 99%

“…Two different human CB2 receptor isoforms (hCB2A and hCB2B) have been identified [ 33 , 34 ]. hCB2B was mostly observed in the spleen and leukocytes, whereas hCB2A expression was mainly detected in the testis and brain [ 33 , 34 ].…”

Section: The Cannabinoid Type 2 (Cb2) Receptors In Pdmentioning

confidence: 99%

“…Furthermore, it has been suggested that CB2 receptors could represent a promising therapeutic target not only in PD but also in different other neurodegenerative disorders, such as Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis [ 2 , 30 , 34 , 40 , 41 , 42 , 43 , 44 ].…”

Section: The Cannabinoid Type 2 (Cb2) Receptors In Pdmentioning

confidence: 99%

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The Role of Cannabinoid Type 2 Receptors in Parkinson’s Disease

Basile

Mazzon

2022

Biomedicines

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Parkinson’s disease (PD) is the second most frequent neurodegenerative disease and currently represents a clear unmet medical need. Therefore, novel preventive and therapeutic strategies are needed. Cannabinoid type 2 (CB2) receptors, one of the components of the endocannabinoid system, can regulate neuroinflammation in PD. Here, we review the current preclinical and clinical studies investigating the CB2 receptors in PD with the aim to clarify if these receptors could have a role in PD. Preclinical data show that CB2 receptors could have a neuroprotective action in PD and that the therapeutic targeting of CB2 receptors could be promising. Indeed, it has been shown that different CB2 receptor-selective agonists exert protective effects in different PD models. Moreover, the alterations in the expression of CB2 receptors observed in brain tissues from PD animal models and PD patients suggest the potential value of CB2 receptors as possible novel biomarkers for PD. However, to date, there is no direct evidence of the role of CB2 receptors in PD. Further studies are strongly needed in order to fully clarify the role of CB2 receptors in PD and thus pave the way to novel possible diagnostic and therapeutic opportunities for PD.

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Medicinal Chemistry approach, pharmacology and neuroprotective benefits of CB2R modulators in neurodegenerative diseases

Cited by 15 publications

References 168 publications

Design, synthesis and biological evaluation of novel orthosteric-allosteric ligands of the cannabinoid receptor type 2 (CB2R)

Design, synthesis and biological evaluation of novel orthosteric-allosteric ligands of the cannabinoid receptor type 2 (CB2R)

Roles of the Cannabinoid System in the Basal Ganglia in Parkinson’s Disease

The Role of Cannabinoid Type 2 Receptors in Parkinson’s Disease

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