Adenosine A2AR/A1R Antagonists Enabling Additional H3R Antagonism for the Treatment of Parkinson’s DiseaseClick to copy article linkArticle link copied!
- Stefanie HagenowStefanie HagenowInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Duesseldorf, Universitaets street 1, 40225 Duesseldorf, GermanyMore by Stefanie Hagenow
- Anna AffiniAnna AffiniInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Duesseldorf, Universitaets street 1, 40225 Duesseldorf, GermanyMore by Anna Affini
- Elsa Y. Pioli
- Sonja HinzSonja HinzPharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, GermanyInstitute of Pharmacology and Toxicology, School of Medicine, University of Witten/Herdecke, Center for Biomedical Education and Research (ZBAF), Faculty of Health, Alfred-Herrhausen-Street 50, 58448 Witten, GermanyMore by Sonja Hinz
- Yan ZhaoYan ZhaoLaboratory of Integrative Physiology of the Brain Arousal Systems, Lyon Neuroscience Research Center, INSERM UI028, CNRS UMR 5292, Claude Bernard University, 8 Avenue Rockefeller, 69373 Lyon, FranceMore by Yan Zhao
- Gregory Porras
- Vigneshwaran NamasivayamVigneshwaran NamasivayamPharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, GermanyMore by Vigneshwaran Namasivayam
- Christa E. MüllerChrista E. MüllerPharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, GermanyMore by Christa E. Müller
- Jian-Sheng LinJian-Sheng LinLaboratory of Integrative Physiology of the Brain Arousal Systems, Lyon Neuroscience Research Center, INSERM UI028, CNRS UMR 5292, Claude Bernard University, 8 Avenue Rockefeller, 69373 Lyon, FranceMore by Jian-Sheng Lin
- Erwan BezardErwan BezardMotac Neuroscience Limited, SK10 4TF Macclesfield, U.K.Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, FranceCNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, FranceMore by Erwan Bezard
- Holger Stark*Holger Stark*Email: [email protected]. Phone: +49 211 8110478.Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Duesseldorf, Universitaets street 1, 40225 Duesseldorf, GermanyMore by Holger Stark
Abstract
Adenosine A1/A2A receptors (A1R/A2AR) represent targets in nondopaminergic treatment of motor disorders such as Parkinson’s disease (PD). As an innovative strategy, multitargeting ligands (MTLs) were developed to achieve comprehensive PD therapies simultaneously addressing comorbid symptoms such as sleep disruption. Recognizing the wake-promoting capacity of histamine H3 receptor (H3R) antagonists in combination with the “caffeine-like effects” of A1R/A2AR antagonists, we designed A1R/A2AR/H3R MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl H3R pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar H3R affinities (Ki < 55 nM). Compound 4 (ST-2001, Ki (A1R) = 11.5 nM, Ki (A2AR) = 7.25 nM) and 12 (ST-1992, Ki (A1R) = 11.2 nM, Ki (A2AR) = 4.01 nM) were evaluated in vivo. l-DOPA-induced dyskinesia was improved after administration of compound 4 (1 mg kg–1, i.p. rats). Compound 12 (2 mg kg–1, p.o. mice) increased wakefulness representing novel pharmacological tools for PD therapy.
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