Patients with Parkinson's disease are missing the chemical neurotransmitter dopamine. This occurs as a result of destructive changes in an area of the brain responsible for making dopamine, the basal ganglia. Patients with the disease experience, rigid muscles, stooped posture, and a shuffling-type walk (gait).
In this study researchers plan to evaluate the effectiveness of the drug eliprodil for the treatment of Parkinson's Disease. Eliprodil works by blocking special receptors (NMDA) that are associated with the symptoms of Parkinson's Disease.

开始日期1999-03-01

申办/合作机构

National Institute of Neurological Disorders & Stroke

100 项与依利罗地相关的临床结果

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100 项与依利罗地相关的转化医学

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100 项与依利罗地相关的专利（医药）

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125

项与依利罗地相关的文献（医药）

2023-12-20·ACS chemical neuroscience

Characterization of (R)- and (S)-[¹⁸F]OF-NB1 in Rodents as Positron Emission Tomography Probes for Imaging GluN2B Subunit-Containing N-Methyl-d-Aspartate Receptors

Article

作者: Gruber, Stefan ; Gisler, Livio ; Sippl, Wolfgang ; Liang, Steven H ; Haider, Ahmed ; Keller, Claudia ; Wallimann, Rahel ; Ametamey, Simon M ; Ahmed, Hazem ; Elghazawy, Nehal H

The N-methyl-d-aspartate receptor (NMDAR) subtype 2B (GluN1/2B) is implicated in various neuropathologies. Given the lack of a validated radiofluorinated positron emission tomography (PET) probe for the imaging of GluN1/2B receptors, we comprehensively investigated the enantiomers of [¹⁸F]OF-NB1 in rodents. Particularly, the (R)- and (S)- enantiomers were evaluated using in silico docking, in vitro autoradiography, in vivo PET imaging, and ex vivo biodistribution studies. A select panel of GluN1/2B antagonists (CP-101,606, CERC-301, and eliprodil) and the off-target sigma-1 receptor ligands (fluspidine and SA4503) were used to determine the specificity and selectivity of the tested enantiomers. Additionally, a nonmetal-mediated radiofluorination strategy was devised that harnesses the potential of diaryliodoniums in the nucleophilic radiofluorination of nonactivated aromatic compounds. Both enantiomers exhibited known GluN1/2B binding patterns; however, the R-enantiomer showed higher GluN1/2B-specific accumulation in rodent autoradiography and higher brain uptake in PET imaging experiments compared to the S-enantiomer. Molecular simulation studies provided further insights with respect to the difference in binding, whereby a reduced ligand-receptor interaction was observed for the S-enantiomer. Nonetheless, both enantiomers showed dose dependency when two different doses (1 and 5 mg/kg) of the GluN1/2B antagonist, CP-101,606, were used in the PET imaging study. Taken together, (R)-[¹⁸F]OF-NB1 appears to exhibit the characteristics of a suitable PET probe for imaging of GluN2B-containing NMDARs in clinical studies.

2022-07-01·European journal of medicinal chemistry1区 · 医学

Synthesis and biological evaluation of conformationally restricted GluN2B ligands derived from eliprodil

1区 · 医学

Article

作者: Wünsch, Bernhard ; Seebohm, Guiscard ; Daniliuc, Constantin ; Schepmann, Dirk ; Schreiber, Julian A ; Bechthold, Elena ; Ritter, Nadine

N-Methyl-d-aspartate (NMDA) receptors containing one or two GluN2B subunits play a crucial role in a variety of neurodegenerative diseases, such as Alzheimer's and Huntington's disease. In order to increase selectivity for GluN2B NMDA receptors, the piperidine ring of eliprodil (2) was conformationally restricted by introduction of an ethano bridge across C-2 and C-6 resulting in a tropane scaffold. Benzylidenetropanes 15 and 16 and benzyltropanes 17 and 18 were prepared by nucleophilic opening of enantiomerically pure phenyloxiranes 13 and 14 with racemic secondary amines (Z/E)-11 and diastereomeric mixtures (r/s)-12. The diastereomers were separated by preparative HPLC to obtain enantiomerically pure test compounds 15-18. The absolute and relative configuration of the products were determined by X-ray crystal structure analysis. Benzylidenetropanes 15 and 16 as well as benzyltropanes 17 and 18 display very high GluN2B affinity in receptor binding studies. Benzylidinetropanes with the phenyl moiety oriented towards C-5 of the tropane system showed higher GluN2B affinity than their analogs with the phenyl moiety oriented towards C-1. In benzyltropanes endo-configured stereoisomers exhibit higher GluN2B affinity than exo-configured diastereomers. Unfortunately, tropanes 15-18 show also high σ₁ and σ₂ affinity with the same trends for the stereoisomers as for GluN2B affinity. The high-affinity GluN2B ligand (R,r)-17b was able to inhibit the ion flux in two-electrode voltage clamp experiments using GluN1a/GluN2B expressing oocytes.

2022-02-01·European journal of medicinal chemistry1区 · 医学

Synthesis of tropane-based σ1 receptor antagonists with antiallodynic activity

1区 · 医学

Article

作者: Wünsch, Bernhard ; Daniliuc, Constantin ; Nieto, Francisco Rafael ; Grey, Lucie ; Seebohm, Guiscard ; González-Cano, Rafael ; Schreiber, Julian A ; Schepmann, Dirk ; Bechthold, Elena ; Ritter, Nadine

Following the concept of conformational restriction to obtain high affinity σ₁ ligands, the piperidine ring of eliprodil was replaced by the bicyclic tropane system and an exocyclic double bond was introduced. The envisaged benzylidenetropanes 9 were prepared by conversion of tropanone 10 into the racemic mixture of (Z)-14 and (E)-14. Reaction of racemate (Z)-14/(E)-14 with enantiomerically pure (R)- or (S)-configured 2-phenyloxirane provided mixtures of diastereomeric β-aminoalcohols (R,Z)-9 and (R,E)-9 as well as (S,Z)-9 and (S,E)-9, which were separated by chiral HPLC, respectively. X-ray crystal structure analysis of (S,Z)-9 allowed the unequivocal assignment of the configuration of all four stereoisomers. In receptor binding studies with radioligands, (R,E)-9 and (S,Z)-9 showed subnanomolar σ₁ affinity with eudismic ratios of 8.3 and 40. In both compounds the 4-fluorophenyl moiety is oriented towards (S)-configured C-5 of the tropane system. Both compounds display high selectivity for the σ₁ receptor over the σ₂ subtype but moderate selectivity over GluN2B NMDA receptors. In vivo, (R,E)-9 (K_i(σ₁) = 0.80 nM) showed high antiallodynic activity in the capsaicin assay. The effect of (R,E)-9 could be reversed by pre-administration of the σ₁ agonist PRE-084 confirming the σ₁ antagonistic activity of (R,E)-9.

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外链

KEGG	Wiki	ATC	Drug Bank
-	依利罗地	-	DB12869

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
脑损伤	临床3期	-	Sanofi	-
颅脑损伤	临床3期	美国	-	-
颅脑损伤	临床3期	欧盟	-	-
脑卒中	临床3期	-	Sanofi-Synthélabo SA	-
多发性硬化症	临床前	法国	Sanofi-Synthelabo, Inc.	-
肌萎缩侧索硬化	药物发现	法国	Synthélabo SA	-