Document Detail

Design, synthesis and biological evaluation of bivalent ligands against A(1)-D(1) receptor heteromers.
MedLine Citation:
PMID:  23334237     Owner:  NLM     Status:  MEDLINE    
AIM: To design and synthesize bivalent ligands for adenosine A1-dopamine D1 receptor heteromers (A1-D1R), and evaluate their pharmacological activities.
METHODS: Bivalent ligands and their corresponding A1R monovalent ligands were designed and synthesized. The affinities of the bivalent ligands for A1R and D1R in rat brain membrane preparation were examined using radiolabeled binding assays. To demonstrate the formation of A1-D1R, fluorescence resonance energy transfer (FRET) was conducted in HEK293 cells transfected with D1-CFP and A1-YFP. Molecular modeling was used to analyze the possible mode of protein-protein and protein-ligand interactions.
RESULTS: Two bivalent ligands for A1R and D1R (20a, 20b), as well as the corresponding A1R monovalent ligands (21a, 21b) were synthesized. In radiolabeled binding assays, the bivalent ligands showed affinities for A1R 10-100 times higher than those of the corresponding monovalent ligands. In FRET experiments, the bivalent ligands significantly increased the heterodimerization of A1R and D1R compared with the corresponding monovalent ligands. A heterodimer model with the interface of helixes 3, 4, 5 of A1R and helixes 1, 6, 7 from D1R was established with molecular modeling. The distance between the two ligand binding sites in the heterodimer model was approximately 48.4 Å, which was shorter than the length of the bivalent ligands.
CONCLUSION: This study demonstrates the existence of A1-D1R in situ and a simultaneous interaction of bivalent ligands with both the receptors.
Jian Shen; Lei Zhang; Wan-ling Song; Tao Meng; Xin Wang; Lin Chen; Lin-yin Feng; Ye-chun Xu; Jing-kang Shen
Related Documents :
24949977 - Glucocorticoid receptor function regulated by coordinated action of the hsp90 and hsp70...
24595807 - A conformational analysis of mouse nalp3 domain structures by molecular dynamics simula...
23437107 - Crystal structure of silkworm bombyx mori jhbp in complex with 2-methyl-2,4-pentanediol...
24392667 - Disclosure of key stereoelectronic factors for efficient h2 binding and cleavage in the...
14617157 - Mapping the binding domains on meningococcal opa proteins for ceacam1 and cea receptors.
6300067 - Photoaffinity labeling of specific alpha-thrombin binding sites on chinese hamster lung...
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-21
Journal Detail:
Title:  Acta pharmacologica Sinica     Volume:  34     ISSN:  1745-7254     ISO Abbreviation:  Acta Pharmacol. Sin.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-05     Completed Date:  2013-12-27     Revised Date:  2014-07-31    
Medline Journal Info:
Nlm Unique ID:  100956087     Medline TA:  Acta Pharmacol Sin     Country:  United States    
Other Details:
Languages:  eng     Pagination:  441-52     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Adenosine A2 Receptor Antagonists / chemical synthesis,  chemistry,  pharmacology*
Binding, Competitive
Brain / metabolism
Dopamine Agonists / chemical synthesis,  chemistry,  pharmacology*
Drug Design*
Fluorescence Resonance Energy Transfer
HEK293 Cells
Molecular Docking Simulation
Molecular Structure
Protein Binding
Protein Multimerization*
Rats, Wistar
Receptor, Adenosine A1 / chemistry,  metabolism*
Receptors, Dopamine D1 / agonists,  chemistry,  metabolism*
Structure-Activity Relationship
Reg. No./Substance:
0/Adenosine A2 Receptor Antagonists; 0/Dopamine Agonists; 0/Ligands; 0/Receptor, Adenosine A1; 0/Receptors, Dopamine D1

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Zeolite-based hemostat QuikClot releases calcium into blood and promotes blood coagulation in vitro.
Next Document:  Strontium ranelate reduces cartilage degeneration and subchondral bone remodeling in rat osteoarthri...