Structure-guided design of A(3) adenosine receptor-selective nucleosides: combination of 2-arylethynyl and bicyclo[3.1.0]hexane substitutions. J Med Chem 2012 May 24;55(10):4847-60
Date
05/09/2012Pubmed ID
22559880Pubmed Central ID
PMC3371665DOI
10.1021/jm300396nScopus ID
2-s2.0-84861499550 (requires institutional sign-in at Scopus site) 80 CitationsAbstract
(N)-Methanocarba adenosine 5'-methyluronamides containing known A(3) AR (adenosine receptor)-enhancing modifications, i.e., 2-(arylethynyl)adenine and N(6)-methyl or N(6)-(3-substituted-benzyl), were nanomolar full agonists of human (h) A(3)AR and highly selective (K(i) ∼0.6 nM, N(6)-methyl 2-(halophenylethynyl) analogues 13 and 14). Combined 2-arylethynyl-N(6)-3-chlorobenzyl substitutions preserved A(3)AR affinity/selectivity in the (N)-methanocarba series (e.g., 3,4-difluoro full agonist MRS5698 31, K(i) 3 nM, human and mouse A(3)) better than that for ribosides. Polyaromatic 2-ethynyl N(6)-3-chlorobenzyl analogues, such as potent linearly extended 2-p-biphenylethynyl MRS5679 34 (K(i) hA(3) 3.1 nM; A(1), A(2A), inactive) and fluorescent 1-pyrene adduct MRS5704 35 (K(i) hA(3) 68.3 nM), were conformationally rigid; receptor docking identified a large, mainly hydrophobic binding region. The vicinity of receptor-bound C2 groups was probed by homology modeling based on recent X-ray structure of an agonist-bound A(2A)AR, with a predicted helical rearrangement requiring an agonist-specific outward displacement of TM2 resembling opsin. Thus, the X-ray structure of related A(2A)AR is useful in guiding the design of new A(3)AR agonists.
Author List
Tosh DK, Deflorian F, Phan K, Gao ZG, Wan TC, Gizewski E, Auchampach JA, Jacobson KAAuthors
John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinTina C. Wan PhD Research Scientist II in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdenosineAdenosine A3 Receptor Agonists
Alkynes
Animals
Bridged Bicyclo Compounds
CHO Cells
Cricetinae
Cricetulus
Crystallography, X-Ray
Drug Design
HEK293 Cells
Hexanes
Humans
Mice
Models, Molecular
Molecular Conformation
Protein Conformation
Radioligand Assay
Receptor, Adenosine A3
Stereoisomerism
Structure-Activity Relationship
