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Hybrid ortho/allosteric ligands for the adenosine A(1) receptor

Narlawar, Rajeshwar; Lane, J Robert; Doddareddy, Munikumar; Lin, Judy; Brussee, Johannes; Ijzerman, Adriaan P


Rajeshwar Narlawar

Associate Professor

Munikumar Doddareddy

Judy Lin

Johannes Brussee

Adriaan P Ijzerman


Many G protein-coupled receptors (GPCRs), including the adenosine A(1) receptor (A(1)AR), have been shown to be allosterically modulated by small molecule ligands. So far, in the absence of structural information, the exact location of the allosteric site on the A(1)AR is not known. We synthesized a series of bivalent ligands (4) with an increasing linker length between the orthosteric and allosteric pharmacophores and used these as tools to search for the allosteric site on the A(1)AR. The compounds were tested in both equilibrium radioligand displacement and functional assays in the absence and presence of a reference allosteric enhancer, (2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluoromethyl)phenyl]methanone, PD81,723 (1). Bivalent ligand N(6)-[2-amino-3-(3,4-dichlorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl-9-nonyloxy-4-phenyl]-adenosine 4h (LUF6258) with a 9 carbon atom spacer did not show significant changes in affinity or potency in the presence of 1, indicating that this ligand bridged both sites on the receptor. Furthermore, 4h displayed an increase in efficacy, but not potency, compared to the parent, monovalent agonist 2. From molecular modeling studies, we speculate that the allosteric site of the A(1)AR is located in the proximity of the orthosteric site, possibly within the boundaries of the second extracellular loop of the receptor.


Narlawar, R., Lane, J. R., Doddareddy, M., Lin, J., Brussee, J., & Ijzerman, A. P. (2010). Hybrid ortho/allosteric ligands for the adenosine A(1) receptor. Journal of Medicinal Chemistry, 53(8), 3028-3037.

Journal Article Type Article
Online Publication Date Mar 26, 2010
Publication Date Apr 22, 2010
Deposit Date Apr 22, 2020
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 53
Issue 8
Pages 3028-3037
Public URL
Publisher URL