The endocannabinoid system dual-target ligand N-cycloheptyl-1,2-dihydro-5-bromo-1-(4-fluorobenzyl)-6-methyl-2-oxo-pyridine-3-carboxamide improves disease severity in a mouse model of multiple sclerosis

Arena, Chiara; Gado, Francesca; Mannelli, Lorenzo Di Cesare; Cervetto, Chiara; Carpi, Sara; Reynoso-Moreno, Inés; Polini, Beatrice; Vallini, Erika; Chicca, S.; Lucarini, Elena; Bertini, Simone; D’Andrea, Felicia; Digiacomo, Maria; Poli, Giulio; Tuccinardi, Tiziano; Macchia, Marco; Gertsch, Jürg; Marcoli, Manuela; Nieri, Paola; Ghelardini, Carla; Chicca, Andrea; Manera, Clementina

doi:10.1016/j.ejmech.2020.112858

Cited by 16 publications

(17 citation statements)

References 85 publications

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“…However, it should be emphasized that the findings reported here primarily reflect the intrinsic potential of these compounds to activate CB 1 . Ideally, in vivo studies examining conventional cannabinoid effects, like body temperature and heart rate changes, 30 hyperthermia‐induced seizures, 35 the cold plate test, 36 or the tetra test (assessing locomotion, catalepsy, body temperature, and analgesia) 37 are used to further substantiate these findings. In this context, it needs to be mentioned that in vivo, the net impact of these compounds will be determined by many factors, including bioavailability, metabolic stability, the formation of active metabolites, blood brain barrier penetration, and off‐target effects.…”

Section: Discussionmentioning

confidence: 99%

Systematic evaluation of a panel of 30 synthetic cannabinoid receptor agonists structurally related to MMB‐4en‐PICA, MDMB‐4en‐PINACA, ADB‐4en‐PINACA, and MMB‐4CN‐BUTINACA using a combination of binding and different CB₁ receptor activation assays—Part II: Structure activity relationship assessment via a β‐arrestin recruitment assay

Grafinger

Cannaert

Ametovski

et al. 2021

Drug Testing and Analysis

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Synthetic cannabinoid receptor agonists (SCRAs) are the second largest class of new psychoactive substances (NPS) and are associated with serious adverse effects and even death. Despite this, little pharmacological data are available for many of the most recent SCRAs. This study consists of three different parts, aiming to systematically evaluate a panel of 30 SCRAs using binding and different in vitro human cannabinoid 1 receptor (CB1) activation assays. The present Part II investigated the SCRA analogs for their CB1 activation via a β‐arrestin recruitment assay. The panel was systematically designed to include key structural sub‐features of recent SCRAs. Thus, the 4‐pentenyl tail of MMB‐4en‐PICA and MDMB‐4en‐PINACA was retained while incorporating varying head groups from other prevalent SCRAs, including amides and esters of L‐valine, L‐tert‐leucine, and L‐phenylalanine, and adamantyl and cumyl moieties. All 30 SCRAs activated CB1, with indazoles generally showing the greatest potency (EC50 = 1.88–281 nM), followed by indoles (EC50 = 11.5–2293 nM), and the corresponding 7‐azaindoles (EC50 = 62.4–9251 nM). Several subunit‐linked structure–activity relationships were identified: (i) tert‐leucine‐functionalized SCRAs were more potent than the corresponding valine derivatives; (ii) no major difference in potency or efficacy was observed between tert‐leucine/valine‐derived amides and the corresponding methyl esters; however, phenylalanine analogs were affected by this change; and (iii) minor structural changes to the 4‐pentenyl substituent had little influence on activity. These findings elucidate structural features that modulate the CB1 activation potential of currently prevalent SCRAs and a systematic panel of analogs, some of which may appear in NPS markets in future.

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Section: Discussionmentioning

confidence: 99%

Systematic evaluation of a panel of 30 synthetic cannabinoid receptor agonists structurally related to MMB‐4en‐PICA, MDMB‐4en‐PINACA, ADB‐4en‐PINACA, and MMB‐4CN‐BUTINACA using a combination of binding and different CB₁ receptor activation assays—Part II: Structure activity relationship assessment via a β‐arrestin recruitment assay

Grafinger

Cannaert

Ametovski

et al. 2021

Drug Testing and Analysis

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“…Nevertheless, only a limited number of ligands are clinically applicable. Our group has already developed a small library of CBR orthosteric ligands. − Among them the 2-oxo-pyridine derivative FM-6b (Figure ) was the most promising, acting as a full agonist at both CBRs with high affinity . Functional studies also revealed a significant activity of FM-6b on neuroinflammation, glutamate-mediated excitotoxicity and neuropathic pain .…”

Section: Introductionmentioning

confidence: 99%

“…Notably, both parent compounds were modified at position N(1) on their central core structure to allow the introduction of a designed linker. Concerning to this aspect, previous structural activity relation studies indicated this position as the most suitable to chemical modifications without significantly compromising activity. ,− Structurally, the linker consists of a disubstituted 1,2,3- triazole ring connected to two alkyl chain of variable length at position N(1) and C(4), respectively. Among nitrogen-containing heterocyclic compounds, 1,2,3-triazoles have found broad applications in drug discovery .…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Activity of New CB2 Receptor Ligands: from Orthosteric and Allosteric Modulators to Dualsteric/Bitopic Ligands

et al. 2022

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The design of dualsteric/bitopic agents as single chemical entities able to simultaneously interact with both the orthosteric and an allosteric binding site represents a novel approach in medicinal chemistry. Biased dualsteric/bitopic agents could enhance certain signaling pathways while diminishing the others that cause unwanted side effects. We have designed, synthesized, and functionally characterized the first CB2R heterobivalent bitopic ligands. In contrast to the parent orthosteric compound, our bitopic ligands selectively target CB2R versus CB1R and show a functional selectivity for the cAMP signaling pathway versus βarrestin2 recruitment. Moreover, the most promising bitopic ligand FD-22a displayed anti-inflammatory activity in a human microglial cell inflammatory model and antinociceptive activity in vivo in an experimental mouse model of neuropathic pain. Finally, computational studies clarified the binding mode of these compounds inside the CB2R, further confirming their bitopic nature.

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“…Therefore, CB receptors are considered potential pharmacological targets to reduce EAE/MS symptoms. Early experiments using nonselective CB1/CB2 receptor agonists such as WIN-55212-2 and either FAAH or MAGL inhibitors have shown a significant protection against EAE development in mice and rats, where those effects were mediated either through only one type of CB receptors (CB1 or CB2 receptor) or both. ,,− …”

Section: Discussionmentioning

confidence: 99%

Selective Endocannabinoid Reuptake Inhibitor WOBE437 Reduces Disease Progression in a Mouse Model of Multiple Sclerosis

Reynoso-Moreno

Tietz

Vallini

et al. 2021

ACS Pharmacol. Transl. Sci.

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The modulation of the endocannabinoid system (ECS) has shown positive results in animal models of multiple sclerosis (MS) and immune and inflammatory disorders. However, chronic administration of CB1 receptor agonists and degrading enzyme inhibitors can lead to CB1 receptor desensitization and sedation. WOBE437 is the prototype of a new class of ECS modulators named selective endocannabinoid reuptake inhibitors (SERIs), which mildly and selectively increase central endocannabinoid levels with a self-limiting mode of action. In previous studies, WOBE437 demonstrated analgesic, anxiolytic, and anti-inflammatory effects. Here, we tested the therapeutic potential of WOBE437 in a clinically relevant mouse model of MS (experimental autoimmune encephalomyelitis). C57BL/6 mice were administered WOBE437 (10 mg/kg, 20 days) or vehicle using two therapeutic options: (1) starting the treatment at the disease onset or (2) before reaching the peak of the disease. In both strategies, WOBE437 significantly reduced disease severity and accelerated recovery through CB1 and CB2 receptor-dependent mechanisms. At the peak of the disease, WOBE437 increased endocannabinoid levels in the cerebellum, concurring with a reduction of central nervous system (CNS)-infiltrating immune cells and lower microglial proliferation. At the end of treatment, endocannabinoid levels were mildly increased in brain, cerebellum, and plasma of WOBE437-treated mice, without desensitization of CB1 receptor in the brain and cerebellum. In a mouse model of spasticity (Straub test), WOBE437 (10 mg/kg) induced significant muscle relaxation without eliciting the typical sedative effects associated with muscle relaxants or CB1 receptor agonists. Collectively, our results show that WOBE437 (and SERIs) may represent a novel therapeutic strategy for slowing MS progression and control major symptoms.

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The endocannabinoid system dual-target ligand N-cycloheptyl-1,2-dihydro-5-bromo-1-(4-fluorobenzyl)-6-methyl-2-oxo-pyridine-3-carboxamide improves disease severity in a mouse model of multiple sclerosis

Cited by 16 publications

References 85 publications

Design, Synthesis, and Biological Activity of New CB2 Receptor Ligands: from Orthosteric and Allosteric Modulators to Dualsteric/Bitopic Ligands

Selective Endocannabinoid Reuptake Inhibitor WOBE437 Reduces Disease Progression in a Mouse Model of Multiple Sclerosis

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