Synthesis and pharmacological evaluation of fluorinated benzo[7]annulen‐7‐amines as GluN2B‐selective NMDA receptor antagonists

Thum, Simone; Schepmann, Dirk; Reinoso, Raquel F.; Álvarez, Inés; Ametamey, Simon M.; Wünsch, Bernhard

doi:10.1002/jlcr.3718

Cited by 8 publications

(4 citation statements)

References 39 publications

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“…The affinity toward σ 2 receptors was also recorded in receptor binding studies. Since the pharmacophore of σ ligands is similar to the pharmacophore of ligands interacting with the ifenprodil binding site of GluN2B receptors and we often observe cross-reactivity, − the interaction with GluN2B subunit-containing NMDA receptors was included in this study. The aminodiols 8–11 and their bicyclic analogues 13–16 exhibit high selectivity for σ 1 receptors over σ 2 receptors and the ifenprodil binding site of GluN2B-NMDA receptors.…”

Section: Resultsmentioning

confidence: 99%

Conformationally Restricted σ₁ Receptor Antagonists from (−)-Isopulegol

et al. 2023

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Antagonists at σ1 receptors have great potential for the treatment of neuropathic pain. Starting from monoterpene (−)-isopulegol (1), aminodiols 8–11 were obtained and transformed into bicyclic 13–16 and tricyclic ligands 19–22. Aminodiols 8–11 showed higher σ1 affinity than the corresponding bicyclic 13–16 and tricyclic derivatives 19–22. (R)-configuration in the side chain of aminodiols (8 and 10) led to higher σ1 affinity than (S)-configuration (9 and 11). 4-Benzylpiperidines (b-series) revealed higher σ1 affinity than 4-phenylbutylamines (a-series). Aminodiol 8b showed very high σ1 affinity (K i = 1.2 nM), excellent selectivity over σ2 receptors, and promising logD 7.4 (3.05) and lipophilic ligand efficiency (5.87) values. Molecular dynamics simulations were conducted to analyze the σ1 affinity and selectivity on an atomistic level. In the capsaicin assay, 8b exhibited similar antiallodynic activity to the prototypical σ1 antagonist S1RA. The antiallodynic activity of 8b was removed by co-application of the σ1 agonist PRE-084, proving σ1 antagonism being involved in the antiallodynic effect.

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Section: Resultsmentioning

confidence: 99%

Conformationally Restricted σ₁ Receptor Antagonists from (−)-Isopulegol

et al. 2023

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“…Fluorinated benzo[ 7 ]annulen-7-amines were designed and synthesized as selective GluN2B/NMDAR antagonists by Thum et al . [ 105 ]. Diverse substituted benzo[ 7 ]annulen-7-amines were then utilized to develop structure–affinity relationships of GluN2B antagonists.…”

Section: Recent Progress In the Development Of Glun2b Selective Ligandsmentioning

confidence: 99%

GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics

Ugale

Deshmukh

Lokwani³

et al. 2023

Mol Divers

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N -methyl- D -aspartate receptors (NMDARs) play essential roles in vital aspects of brain functions. NMDARs mediate clinical features of neurological diseases and thus, represent a potential therapeutic target for their treatments. Many findings implicated the GluN2B subunit of NMDARs in various neurological disorders including epilepsy, ischemic brain damage, and neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, Huntington’s chorea, and amyotrophic lateral sclerosis. Although a large amount of information is growing consistently on the importance of GluN2B subunit, however, limited recent data is available on how subunit-selective ligands impact NMDAR functions, which blunts the ability to render the diagnosis or craft novel treatments tailored to patients. To bridge this gap, we have focused on and summarized recently reported GluN2B selective ligands as emerging subunit-selective antagonists and modulators of NMDAR. Herein, we have also presented an overview of the structure–function relationship for potential GluN2B/NMDAR ligands with their binding sites and connection to CNS functionalities. Understanding of design rules and roles of GluN2B selective compounds will provide the link to medicinal chemists and neuroscientists to explore novel neurotherapeutic strategies against dysfunctions of glutamatergic neurotransmission. Graphical abstract

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“…The compound exhibited 2 nM K D for GluN2B receptors expressed in mouse fibroblasts. Of special interest was their demonstration that the ligand did not interact with σ 1 receptors, which has been a limitation of several GluN2B ligands, including a series of tetra-hydro-1 H -3-benzazepines [ 81 ] and fluorinated benzo[7]annulen-7-amines [ 82 ]. No radiolabelled metabolites of [ 11 C]GluN2B-SMe ( 44 ) were detected in rat brain at 30 min after tracer injection, and preblocking with ifenprodil decreased the cerebral SUV from 3 to about 0.5.…”

Section: Glutamate Receptorsmentioning

confidence: 99%

A Review of Molecular Imaging of Glutamate Receptors

et al. 2020

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Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (N-methyl-D-aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.

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Synthesis and pharmacological evaluation of fluorinated benzo[7]annulen‐7‐amines as GluN2B‐selective NMDA receptor antagonists

Cited by 8 publications

References 39 publications

Conformationally Restricted σ₁ Receptor Antagonists from (−)-Isopulegol

Conformationally Restricted σ₁ Receptor Antagonists from (−)-Isopulegol

GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics

A Review of Molecular Imaging of Glutamate Receptors

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Synthesis and pharmacological evaluation of fluorinated benzo[7]annulen‐7‐amines as GluN2B‐selective NMDA receptor antagonists

Cited by 8 publications

References 39 publications

Conformationally Restricted σ1 Receptor Antagonists from (−)-Isopulegol

Conformationally Restricted σ1 Receptor Antagonists from (−)-Isopulegol

GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics

A Review of Molecular Imaging of Glutamate Receptors

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Conformationally Restricted σ₁ Receptor Antagonists from (−)-Isopulegol

Conformationally Restricted σ₁ Receptor Antagonists from (−)-Isopulegol