Adenosine A2AR/A1R Antagonists Enabling Additional H3R Antagonism for the Treatment of Parkinson’s Disease.

Stefanie Hagenow, Anna Affini, Elsa Y. Pioli, Sonja Hinz, Yan Zhao, Gregory Porras, Vigneshwaran Namasivayam, Christa E. Müller, Jian-Sheng Lin, Erwan Bezard, Holger Stark
J. Med. Chem.. 2021-06-09; :
DOI: 10.1021/acs.jmedchem.0c00914

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Hagenow S(1), Affini A(1), Pioli EY(2), Hinz S(3)(4), Zhao Y(5), Porras G(2), Namasivayam V(3), Müller CE(3), Lin JS(5), Bezard E(2)(6)(7), Stark H(1).

Author information:
(1)Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University
Duesseldorf, Universitaets street 1, 40225 Duesseldorf, Germany.
(2)Motac Neuroscience Limited, SK10 4TF Macclesfield, U.K.
(3)PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal
Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
(4)Institute 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, Germany.
(5)Laboratory 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, France.
(6)Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000
Bordeaux, France.
(7)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux,

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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