Prodrug Approach toward the Development of a PET Radioligand for Imaging the GluN2A Subunits of the NMDA Receptor

Gruber, Stefan; Waser, Valérie; Thiel, Zacharias; Ametamey, Simon M.

doi:10.1021/acs.orglett.1c01274

Cited by 5 publications

(1 citation statement)

References 13 publications

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“…Because of its high blood-brain barrier permeability, 18 F-OF-NB1 builds up in areas of the brain where GluN2B is abundant. When compared with 18 F-PF-NB1, 18 F-OF-NB1 showed greater cerebellum accumulation in ex vivo biodistribution experiments [70][71][72]74,75]. Regarding this, 18 F-OF-NB1 is a promising GluN2B radioligand that is appropriate for PET imaging studies in ALS patients and those with other neurodegenerative diseases [72].…”

Section: The Prototypic Glun2b Inhibitor Ifenprodilmentioning

confidence: 99%

Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes

et al. 2023

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The number of N-Methyl-D-aspartate receptor (NMDAR) linked neurodegenerative diseases such as Alzheimer’s disease and dementia is constantly increasing. This is partly due to demographic change and presents new challenges to societies. To date, there are no effective treatment options. Current medications are nonselective and can lead to unwanted side effects in patients. A promising therapeutic approach is the targeted inhibition of NMDARs in the brain. NMDARs containing different subunits and splice variants display different physiological properties and play a crucial role in learning and memory, as well as in inflammatory or injury processes. They become overactivated during the course of the disease, leading to nerve cell death. Until now, there has been a lack of understanding of the general functions of the receptor and the mechanism of inhibition, which need to be understood in order to develop inhibitors. Ideal compounds should be highly targeted and even splice-variant-selective. However, a potent and splice-variant-selective NMDAR-targeting drug has yet to be developed. Recently developed 3-benzazepines are promising inhibitors for further drug development. The NMDAR splice variants GluN1-1b-4b carry a 21-amino-acid-long, flexible exon 5. Exon 5 lowers the NMDAR’s sensitivity to allosteric modulators by probably acting as an NMDAR modulator itself. The role of exon 5 in NMDAR modulation is still poorly understood. In this review, we summarize the structure and pharmacological relevance of tetrahydro-3-benzazepines.

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Section: The Prototypic Glun2b Inhibitor Ifenprodilmentioning

confidence: 99%

Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes

et al. 2023

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Downstream Allosteric Modulation of NMDA Receptors by 3-Benzazepine Derivatives

Ritter,

Disse,

Aymanns

et al. 2023

Mol Neurobiol

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N-Methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for inflammatory or injury processes. Dysregulation of the NMDAR has been linked to diseases like Parkinson’s, Alzheimer’s, schizophrenia, and drug addiction. The development of selective receptor modulators, therefore, constitutes a promising approach for numerous therapeutical applications. Here, we identified (R)-OF-NB1 as a promising splice variant selective NMDAR antagonist. We investigated the interaction of (R)-OF-NB1 and NMDAR from a biochemical, bioinformatical, and electrophysiological perspective to characterize the downstream allosteric modulation of NMDAR by 3-benzazepine derivatives. The allosteric modulatory pathway starts at the ifenprodil binding pocket in the amino terminal domain and immobilizes the connecting α5-helix to the ligand binding domain, resulting in inhibition. In contrast, the exon 5 splice variant GluN1-1b elevates the NMDARs flexibility and promotes the open state of its ligand binding domain.

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Metal & Surfactant-Free oxidation of Quinoxalin-2(1H)-ones: Access to Quinoxaline-2,3-diones

Zang²,

Wang³

et al. 2022

Tetrahedron Letters

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Prodrug Approach toward the Development of a PET Radioligand for Imaging the GluN2A Subunits of the NMDA Receptor

Abstract: Figure 1. Structure of AFA233 and strategic pathways investigated for the preparation of the [ 18 F]AFA233-prodrug. Letter pubs.acs.org/OrgLett

Cited by 5 publications

References 13 publications

Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes

Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes

Downstream Allosteric Modulation of NMDA Receptors by 3-Benzazepine Derivatives

Metal & Surfactant-Free oxidation of Quinoxalin-2(1H)-ones: Access to Quinoxaline-2,3-diones

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