Publications by authors named "Anna Affini"

3 Publications

  • Page 1 of 1

Adenosine AR/AR Antagonists Enabling Additional HR Antagonism for the Treatment of Parkinson's Disease.

J Med Chem 2021 Jun 9;64(12):8246-8262. Epub 2021 Jun 9.

Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Duesseldorf, Universitaets street 1, 40225 Duesseldorf, Germany.

Adenosine A/A receptors (AR/AR) 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 H receptor (HR) antagonists in combination with the "caffeine-like effects" of AR/AR antagonists, we designed AR/AR/HR MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl HR pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar HR affinities ( < 55 nM). Compound (, (AR) = 11.5 nM, (AR) = 7.25 nM) and (, (AR) = 11.2 nM, (AR) = 4.01 nM) were evaluated . l-DOPA-induced dyskinesia was improved after administration of compound (1 mg kg, i.p. rats). Compound (2 mg kg, p.o. mice) increased wakefulness representing novel pharmacological tools for PD therapy.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00914DOI Listing
June 2021

Novel indanone derivatives as MAO B/HR dual-targeting ligands for treatment of Parkinson's disease.

Eur J Med Chem 2018 Mar 16;148:487-497. Epub 2018 Feb 16.

Heinrich Heine University Duesseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetstr. 1, 40225 Duesseldorf, Germany. Electronic address:

The design of multi-targeting ligands was developed in the last decades as an innovative therapeutic concept for Parkinson's disease (PD) and other neurodegenerative disorders. As the monoamine oxidase B (MAO B) and the histamine H receptor (HR) are promising targets for dopaminergic regulation, we synthetized dual-targeting ligands (DTLs) as non-dopaminergic receptor approach for the treatment of PD. Three series of compounds were developed by attaching the HR pharmacophore to indanone-related MAO B motifs, leading to development of MAO B/HR DTLs. Among synthesized indanone DTLs, compounds bearing the 2-benzylidene-1-indanone core structure showed MAO B preferring inhibition capabilities along with nanomolar hHR affinity. Substitution of C5 and C6 position of the 2-benzylidene-1-indanones with lipophilic substituents revealed three promising candidates exhibiting inhibitory potencies for MAO B with IC values ranging from 1931 nM to 276 nM and high affinities at hHR (K < 50 nM). Compound 3f ((E)-5-((4-bromobenzyl)oxy)-2-(4-(3-(piperidin-1-yl)propoxy)benzylidene)-2,3-dihydro-1H-inden-1-one, MAO B IC = 276 nM, hHR K = 6.5 nM) showed highest preference for MAO B over MAO A (SI > 36). Interestingly, IC determinations after preincubation of enzyme and DTLs revealed also nanomolar MAO B potency for 3e (MAO B IC = 232 nM), a structural isomer of 3f, and 3d (MAO B IC = 541 nM), suggesting time-dependent inhibition modes. Reversibility of inhibition for all three compounds were confirmed by dilution studies in excess of substrate. Thus, indanone-substituted derivatives are promising lead structures for the design of MAO B/hHR DTLs as novel therapeutic approach of PD therapy.
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http://dx.doi.org/10.1016/j.ejmech.2018.02.015DOI Listing
March 2018

Multiple Targeting Approaches on Histamine H3 Receptor Antagonists.

Front Neurosci 2016 30;10:201. Epub 2016 May 30.

Stark Lab, Institut fuer Pharmazeutische and Medizinische Chemie, Heinrich-Heine-Universitaet Duesseldorf Duesseldorf, Germany.

With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.
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http://dx.doi.org/10.3389/fnins.2016.00201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884744PMC
June 2016
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