A New Series of 1,3-Dimethylxanthine Based Adenosine A_2A Receptor Antagonists as a Non-Dopaminergic Treatment of Parkinson’s Disease

Title:A New Series of 1,3-Dimethylxanthine Based Adenosine A_2A Receptor Antagonists as a Non-Dopaminergic Treatment of Parkinson’s Disease

Volume: 18 Issue: 5

Author(s): Suman Rohilla, Ranju Bansal*, Puneet Chauhan, Sonja Kachler and Karl-Norbert Klotz

Affiliation:

• University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh,India

Keywords: 8-Chloropropoxyphenylxanthine, A2A receptor, binding assays, catatonia, parkinson`s disease, docking studies.

Abstract: Background: Adenosine receptors (AR) have emerged as competent and innovative nondopaminergic targets for the development of potential drug candidates and thus constitute an effective and safer treatment approach for Parkinson’s disease (PD). Xanthine derivatives are considered as potential candidates for the treatment Parkinson’s disease due to their potent A2A AR antagonistic properties.

Objective: The objectives of the work are to study the impact of substituting N7-position of 8-m/pchloropropoxyphenylxanthine structure on in vitro binding affinity of compounds with various AR subtypes, in vivo antiparkinsonian activity and binding modes of newly synthesized xanthines with A2A AR in molecular docking studies.

Methods: Several new 7-substituted 8-m/p-chloropropoxyphenylxanthine analogues have been prepared. Adenosine receptor binding assays were performed to study the binding interactions with various subtypes and perphenazine induced rat catatonia model was used for antiparkinsonian activity. Molecular docking studies were performed using Schrödinger molecular modeling interface.

Results: 8-para-substituted xanthine 9b bearing an N7-propyl substituent displayed the highest affinity towards A2A AR (Ki = 0.75 μM) with moderate selectivity versus other AR subtypes. 7-Propargyl analogue 9d produced significantly long-lasting antiparkinsonian effects and also produced potent and selective binding affinity towards A2A AR. In silico docking studies further highlighted the crucial structural components required to develop xanthine derived potential A2A AR ligands as antiparkinsonian agents.

Conclusion: A new series of 7-substituted 8-m/p-chloropropoxyphenylxanthines having good affinity for A2A AR and potent antiparkinsonian activity has been developed.

Cite this article as:

Rohilla Suman , Bansal Ranju *, Chauhan Puneet , Kachler Sonja and Klotz Karl-Norbert , A New Series of 1,3-Dimethylxanthine Based Adenosine A_2A Receptor Antagonists as a Non-Dopaminergic Treatment of Parkinson’s Disease, Current Drug Discovery Technologies 2021; 18 (5) : e26082020185360 . https://dx.doi.org/10.2174/1570163817666200827112252

DOI https://dx.doi.org/10.2174/1570163817666200827112252	Print ISSN 1570-1638
Publisher Name Bentham Science Publisher	Online ISSN 1875-6220