Design and in Vivo Characterization of A1 Adenosine Receptor Agonists in the Native Ribose and Conformationally Constrained (N)-Methanocarba Series
| Autor: | Amy C. Rothwell, Zhan-Guo Gao, Julie A. Mattison, Philip Z. Mannes, Zhenzhong Cui, Harsha Rao, Marc L. Reitman, Oksana Gavrilova, Antonella Ciancetta, Amelia Bitant, Kelli L. Vaughan, Veronica Salmaso, Kenneth A. Jacobson, Dilip K. Tosh, John A. Auchampach, David I. Lieberman, Naili Liu |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Agonist Adenosine medicine.drug_class Stereochemistry CHO Cells Inbred C57BL 01 natural sciences NO Adenosine Adenosine A1 Receptor Agonists Animals Bridged Bicyclo Compounds CHO Cells Cricetulus Drug Design HEK293 Cells Macaca fascicularis Molecular Docking Simulation Molecular Structure Structure-Activity Relationship Mice Bridged Bicyclo Compounds Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Cricetulus In vivo Drug Discovery Ribose medicine Humans Animals Structure–activity relationship Receptor 030304 developmental biology 0303 health sciences Molecular Structure biology Riboside biology.organism_classification Adenosine receptor Adenosine A1 Receptor Agonists 0104 chemical sciences Molecular Docking Simulation Macaca fascicularis 010404 medicinal & biomolecular chemistry HEK293 Cells chemistry Drug Design Mice Inbred C57BL Receptor Adenosine A1 Adenosine A1 Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 62:1502-1522 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | (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... |
| Databáze: | OpenAIRE |
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