A New Series of 1,3-Dimethylxanthine Based Adenosine A2A Receptor Antagonists as a Non-Dopaminergic Treatment of Parkinson's Disease.

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.

• Authors: Suman Rohilla, Ranju Bansal, Puneet Chauhan, Sonja Kachler, Karl-Norbert Klotz
• Journal: Current drug discovery technologies (Curr Drug Discov Technol) Vol. 18 Issue 5 Pg. e26082020185360 ( 2021) ISSN: 1875-6220 [Electronic] United Arab Emirates
• PMID: 32860362 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• Adenosine A2 Receptor Antagonists
• Receptor, Adenosine A2A
• Theophylline
• Adenosine

Topics

• Adenosine
• Adenosine A2 Receptor Antagonists (pharmacology)
• Animals
• Molecular Docking Simulation
• Parkinson Disease (drug therapy)
• Rats
• Receptor, Adenosine A2A
• Structure-Activity Relationship
• Theophylline