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J Med Chem. 2019 Feb 14;62(3):1502-1522. doi: 10.1021/acs.jmedchem.8b01662. Epub 2019 Jan 3.

Design and in Vivo Characterization of A1 Adenosine Receptor Agonists in the Native Ribose and Conformationally Constrained (N)-Methanocarba Series.

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Department of Pharmacology , Medical College of Wisconsin , 8701 Watertown Plank Road , Milwaukee , Wisconsin 53226 , United States.
SoBran BioSciences , SoBran, Inc. , 4000 Blackburn Lane , Burtonsville , Maryland 20866 , United States.
Translational Gerontology Branch , National Institute on Aging Intramural Research Program , 16701 Elmer School Road, Building 103 , Dickerson , Maryland 20842 , United States.
School of Pharmacy , Queen's University Belfast , 96 Lisburn Road , Belfast BT9 7BL , U.K.


(N)-Methanocarba ([3.1.0]bicyclohexyl) adenosines and corresponding ribosides were synthesized to identify novel A1 adenosine receptor (A1AR) agonists for CNS or peripheral applications. Human and mouse AR binding was determined to assess the constrained ring system's A1AR compatibility. N6-Dicyclobutylmethyl ribose agonist (9, MRS7469, >2000-fold selective for A1AR) and known truncated N6-dicyclopropylmethyl methanocarba 7 (MRS5474) were drug-like. The pure diastereoisomer of known riboside 4 displayed high hA1AR selectivity. Methanocarba modification reduced A1AR selectivity of N6-dicyclopropylmethyl and endo-norbornyladenosines but increased ribavirin selectivity. Most analogues tested (ip) were inactive or weak in inducing mouse hypothermia, despite mA1AR full agonism and variable mA3AR efficacy, but strong hypothermia by 9 depended on A1AR, which reflects CNS activity (determined using A1AR or A3AR null mice). Conserved hA1AR interactions were preserved in modeling of 9 and methanocarba equivalent 24 (∼400-fold A1AR-selective). Thus, we identified, and characterized in vivo, ribose and methanocarba nucleosides, including with A1AR-enhancing N6-dicyclobutylmethyl-adenine and 1,2,4-triazole-3-carboxamide (40, MRS7451) nucleobases.

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