Design and in Vivo Characterization of A1 Adenosine Receptor Agonists in the Native Ribose and Conformationally Constrained (N)-Methanocarba Series. J Med Chem 2019 Feb 14;62(3):1502-1522
Date
01/04/2019Pubmed ID
30605331Pubmed Central ID
PMC6467784DOI
10.1021/acs.jmedchem.8b01662Scopus ID
2-s2.0-85059756838 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
(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.
Author List
Tosh DK, Rao H, Bitant A, Salmaso V, Mannes P, Lieberman DI, Vaughan KL, Mattison JA, Rothwell AC, Auchampach JA, Ciancetta A, Liu N, Cui Z, Gao ZG, Reitman ML, Gavrilova O, Jacobson KAAuthor
John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdenosineAdenosine A1 Receptor Agonists
Animals
Bridged Bicyclo Compounds
CHO Cells
Cricetulus
Drug Design
HEK293 Cells
Humans
Macaca fascicularis
Male
Mice, Inbred C57BL
Molecular Docking Simulation
Molecular Structure
Receptor, Adenosine A1
Structure-Activity Relationship
