Benzofuranyl-2-imidazoles as imidazoline I2 receptor ligands for Alzheimer's disease

Rodríguez-Arévalo, Sergio; Bagán, Andrea; Griñán-Ferré, Christian; Vasilopoulou, Foteini; Pallàs, Mercè; Brocos‐Mosquera, Iria; Callado, Luís F.; Loza, Marı́a Isabel; Martínez, Antón L.; Brea, José; Pérez, Belén; Molins, Elı́es; Jonghe, Steven De; Daelemans, Dirk; Radan, Milica; Djikić, Teodora; Nikolic, Katarina; Hernández-Hernández, Elena; García-Fuster, M. Julia; Garcı́a-Sevilla, Jesús A.; Escolano, Carmen

doi:10.1016/j.ejmech.2021.113540

Cited by 15 publications

(12 citation statements)

References 56 publications

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“…LSL60101 (garsevil, 10 , Figure 7) was an analog of 2‐BFI, which has an imidazole ring that is connected by position 2 and was first described as an I 2 BS‐selective ligand involved in astrocyte activation and neuronal regeneration. [ 52 ] Compared with 2‐BFI, compound 10 showed decreased affinity (p K i = 6.67) to I 2 BS and lowered selectivity toward α 2 ‐adrenoceptors (Table 2), which was further confirmed by its analogs. [ 52 ] In addition, CR4056 ( 11 , Figure 7), which has a 1 H ‐imidazol moiety, is a first‐in‐class I 2 BS ligand characterized by potent analgesic activity in both animal models and humans and is in clinical phase II studies for osteoarthritis and postoperative dental pain.…”

Section: Perspectives For I2bs Pet Ligand Developmentmentioning

confidence: 91%

“…[ 52 ] Compared with 2‐BFI, compound 10 showed decreased affinity (p K i = 6.67) to I 2 BS and lowered selectivity toward α 2 ‐adrenoceptors (Table 2), which was further confirmed by its analogs. [ 52 ] In addition, CR4056 ( 11 , Figure 7), which has a 1 H ‐imidazol moiety, is a first‐in‐class I 2 BS ligand characterized by potent analgesic activity in both animal models and humans and is in clinical phase II studies for osteoarthritis and postoperative dental pain. [ 3,53 ] Compound 11 exhibited strong agonist efficiency but with a low affinity of 596 nM (IC 50 , [ 3 H]2‐BFI assay) and poor selectivity over MAO‐A (IC 50 = 358 nM).…”

Section: Perspectives For I2bs Pet Ligand Developmentmentioning

confidence: 93%

“…[ 55 ] Changing the p1 cycle from imidazoline to imidazole (compound 10 ) resulted in a significantly reduced affinity to I 2 BS, which was possibly induced by the electrostatic alteration. [ 52 ]…”

Section: Perspectives For I2bs Pet Ligand Developmentmentioning

confidence: 99%

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Visualizing reactive astrocytes: Positron emission tomography imaging ligands for imidazoline‐2 binding sites

Li,

Qiao,

Chen

et al. 2023

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Imidazoline‐2 binding sites (I2BS) exhibit specific expression in reactive astrocytes of the brain and are implicated in various pathophysiological processes, including analgesia, inflammation, Alzheimer's disease, Parkinson's disease, and glial tumors. However, the lack of available protein structural data poses a challenge in the exploration of I2BS functions and pharmacological characterizations, indicating the need for the discovery of selective ligands. As a non‐invasive and translational molecular imaging tool, positron emission tomography (PET) has found wide application in clinical diagnosis and drug discovery. Consequently, several PET ligands have been developed to “visualize” I2BS in the living brain, thereby elucidating the biological implications of I2BS and facilitating I2BS‐directed drug development. This review offers a comprehensive update on I2BS PET ligands, with a focus on their chemotypes and PET imaging outcomes. Furthermore, the review provides a summary of recent I2BS drug discoveries, which could serve as a catalyst for the development of more potent PET ligands.

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Section: Perspectives For I2bs Pet Ligand Developmentmentioning

confidence: 91%

Section: Perspectives For I2bs Pet Ligand Developmentmentioning

confidence: 93%

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Visualizing reactive astrocytes: Positron emission tomography imaging ligands for imidazoline‐2 binding sites

Li,

Qiao,

Chen

et al. 2023

VIEW

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“…Known I 2 -IR ligands share common structural features, namely a 2-substituted imidazoline ( Figure 9 a) [ 57 , 58 , 59 ]. As substitution in the 4 and 5-positions of the imidazoline ring had remained unexplored, we tackled these structural changes to generate new families of I 2 -IR ligands with enhanced pharmacological properties.…”

Section: Receptorsmentioning

confidence: 99%

Heterocycle-Based Multicomponent Reactions in Drug Discovery: From Hit Finding to Rational Design

et al. 2022

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In the context of the structural complexity necessary for a molecule to selectively display a therapeutical action and the requirements for suitable pharmacokinetics, a robust synthetic approach is essential. Typically, thousands of relatively similar compounds should be prepared along the drug discovery process. In this respect, heterocycle-based multicomponent reactions offer advantages over traditional stepwise sequences in terms of synthetic economy, as well as the fast access to chemsets to study the structure activity relationships, the fine tuning of properties, and the preparation of larger amounts for preclinical phases. In this account, we briefly summarize the scientific methodology backing the research line followed by the group. We comment on the main results, clustered according to the targets and, finally, in the conclusion section, we offer a general appraisal of the situation and some perspectives regarding future directions in academic and private research.

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“…On the whole, modulation of I 2 R activity may have potentially interesting clinical applications in vascular disease. Notably, IR research has embarked on its second youth after recent evidence on the therapeutic potential of newly synthesized selective I 2 R ligands as neuroptotective agents ( Ferrari et al, 2011 ; Abás et al, 2017 ; Griñán-Ferré et al, 2019 ; Abás et al, 2020 ; Vasilopoulou et al, 2020 ; Rodriguez-Arévalo et al, 2021 ; Vasilopoulou et al, 2021 ). These new tools may aid in identifying the relevance of I 2 R in vascular health and disease.…”

Section: Introductionmentioning

confidence: 99%

An Imidazoline 2 Receptor Ligand Relaxes Mouse Aorta via Off-Target Mechanisms Resistant to Aging

et al. 2022

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Imidazoline receptors (IR) are classified into three receptor subtypes (I1R, I2R, and I3R) and previous studies showed that regulation of I2R signaling has neuroprotective potential. In order to know if I2R has a role in modulating vascular tone in health and disease, we evaluated the putative vasoactive effects of two recently synthesized I2R ligands, diethyl (1RS,3aSR,6aSR)-5-(3-chloro-4-fluorophenyl)-4,6-dioxo-1-phenyl-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrrole -1-phosphonate (B06) and diethyl [(1-(3-chloro-4-fluorobenzyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-imidazol-4-yl]phosphonate] (MCR5). Thoracic aortas from Oncins France 1 (3- to 4-months-old) and C57BL/6 (3- to 4- and 16- to 17-months-old mice) were mounted in tissue baths to measure isometric tension. In young mice of both strains, MCR5 induced greater relaxations than either B06 or the high-affinity I2R selective ligand 2-(2-benzofuranyl)-2-imidazoline (2-BFI), which evoked marginal responses. MCR5 relaxations were independent of I2R, as IR ligands did not significantly affect them, involved activation of smooth muscle KATP channels and inhibition of L-type voltage-gated Ca2+ channels, and were only slightly modulated by endothelium-derived nitric oxide (negatively) and prostacyclin (positively). Notably, despite the presence of endothelial dysfunction in old mice, MCR5 relaxations were preserved. In conclusion, the present study provides evidence against a functional contribution of I2R in the modulation of vascular tone in the mouse aorta. Moreover, the I2R ligand MCR5 is an endothelium-independent vasodilator that acts largely via I2R-independent pathways and is resistant to aging. We propose MCR5 as a candidate drug for the management of vascular disease in the elderly.

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Benzofuranyl-2-imidazoles as imidazoline I2 receptor ligands for Alzheimer's disease

Cited by 15 publications

References 56 publications

Visualizing reactive astrocytes: Positron emission tomography imaging ligands for imidazoline‐2 binding sites

Visualizing reactive astrocytes: Positron emission tomography imaging ligands for imidazoline‐2 binding sites

Heterocycle-Based Multicomponent Reactions in Drug Discovery: From Hit Finding to Rational Design

An Imidazoline 2 Receptor Ligand Relaxes Mouse Aorta via Off-Target Mechanisms Resistant to Aging

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