A neoceptor approach to unraveling microscopic interactions between the human A2A adenosine receptor and its agonists

39Citations
Citations of this article
29Readers
Mendeley users who have this article in their library.

Abstract

Strategically mutated neoceptors, e.g., with anionic residues in TMs 3 and 7 intended for pairing with positively charged amine-modified nucleosides, were derived from the antiinflammatory A2A adenosine receptor (AR). Adenosine derivatives functionalized at the 5′, 2, and N6 positions were synthesized. The T88D mutation selectively enhanced the binding of the chain-length-optimized 5′-(2-aminoethyl)uronamide but not 5′-(2-hydroxyethyl)uronamide, suggesting a critical role of the positively charged amine. Combination of this modification with the N6-(2- methylbenzyl) group enhanced affinity at the Q89D- and N181D- but not the T88D-A2AAR. Amino groups placed near the 2- or N6-position only slightly affected the binding to mutant receptors. The 5′-hydrazide MRS3412 was 670- and 161-fold enhanced, in binding and functionally, respectively, at the Q89D-A2AAR compared to the wild-type. Thus, we identified and modeled pairs of A2AAR-derived neoceptor-neoligand, which are pharmacologically orthogonal with respect to the native species.

Cite

CITATION STYLE

APA

Jacobson, K. A., Ohno, M., Duong, H. T., Kim, S. K., Tchilibon, S., Česnek, M., … Gao, Z. G. (2005). A neoceptor approach to unraveling microscopic interactions between the human A2A adenosine receptor and its agonists. Chemistry and Biology, 12(2), 237–247. https://doi.org/10.1016/j.chembiol.2004.12.010

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free