Title:A New Series of 1,3-Dimethylxanthine Based Adenosine A2A 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.
