Design, Synthesis, and Evaluation of Novel A2A Adenosine Receptor Agonists
- 16 January 2001
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 44 (4) , 531-539
- https://doi.org/10.1021/jm0003642
Abstract
We have been interested in the design, synthesis, and evaluation of novel adenosine A2A agonists. Through the use of comparative molecular field analysis (CoMFA) we have generated a training model that includes 78 structurally diverse A2A agonists and correlated their affinity for isolated rat brain receptors with differences in their structural and electrostatic properties. We validated this model by predicting the activity of a test set that included 24 additional A2A agonists. Our CoMFA model, which incorporates the physiochemical property of dipole and selects against A1 receptor activity, generated a correlated final model (r2 = 0.891) that provides for enhanced A2A selectivity and predictability. Synthesis, pharmacological evaluation, and modeling of four novel ligands further validate the utility and predictive power (r2 = 0.626) of the CoMFA model.Keywords
This publication has 18 references indexed in Scilit:
- 2-Alkenyl and 2-Alkyl Derivatives of Adenosine and Adenosine-5‘-N-Ethyluronamide: Different Affinity and Selectivity of E- and Z-Diastereomers at A2A Adenosine ReceptorsJournal of Medicinal Chemistry, 1996
- Synthesis of an Orally Active PAF Antagonist of the N-[4-(3-Pyridinyl)butyl]pentqdienamide ClassHETEROCYCLES, 1993
- Nucleosides and nucleotides. 107. 2-(Cycloalkylalkynyl)adenosines: adenosine A2 receptor agonists with potent antihypertensive effectsJournal of Medicinal Chemistry, 1992
- 2-Alkynyl derivatives of adenosine and adenosine-5'-N-ethyluronamide as selective agonists at A2 adenosine receptorsJournal of Medicinal Chemistry, 1992
- Nucleosides and nucleotides. 103. 2-Alkynyladenosines: a novel class of selective adenosine A2 receptor agonists with potent antihypertensive effectsJournal of Medicinal Chemistry, 1992
- Structure and thermal vibrations of adenosine from neutron diffraction data at 123 KActa crystallographica Section B, Structural science, crystal engineering and materials, 1991
- 5-Hydroxytryptamine (5-HT3) receptor antagonists. 1. Indazole and indolizine-3-carboxylic acid derivativesJournal of Medicinal Chemistry, 1990
- Adenosine Receptor Agonists. X-Ray Crystal Structure of Neca 1-(6-Amino-9H-Purin-9-Yl)-1-Deoxy-N-Ethyl-β-D-RibofuranuronamideNucleosides, Nucleotides and Nucleic Acids, 1989
- Facile anhydride synthesis using trichlorotrifluoroacetone hydrateThe Journal of Organic Chemistry, 1986
- Rapid chromatographic technique for preparative separations with moderate resolutionThe Journal of Organic Chemistry, 1978