A Structure–Activity Relationship Study of Bitopic N6-Substituted Adenosine Derivatives as Biased Adenosine A1 Receptor Agonists
| Autor: | Arthur Christopoulos, Peter J. Scammells, Celine Valant, Manuela Jörg, Luigi Aurelio, Shane M. Devine, Leigh Ford, Jo-Anne Baltos, Paul J. White, Anh Nguyen, Lauren T. May |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist Chemistry medicine.drug_class Allosteric regulation Pharmacology Adenosine 03 medical and health sciences Adenosine A1 receptor 030104 developmental biology 0302 clinical medicine TRIF Drug Discovery Functional selectivity medicine Molecular Medicine Structure–activity relationship Pharmacophore 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 61:2087-2103 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The adenosine A1 receptor (A1AR) is a potential novel therapeutic target for myocardial ischemia-reperfusion injury. However, to date, clinical translation of prototypical A1AR agonists has been hindered due to dose limiting adverse effects. Recently, we demonstrated that the biased bitopic agonist 1, consisting of an adenosine pharmacophore linked to an allosteric moiety, could stimulate cardioprotective A1AR signaling in the absence of unwanted bradycardia. Therefore, this study aimed to investigate the structure–activity relationship of compound 1 biased agonism. A series of novel derivatives of 1 were synthesized and pharmacologically profiled. Modifications were made to the orthosteric adenosine pharmacophore, linker, and allosteric 2-amino-3-benzoylthiophene pharmacophore to probe the structure–activity relationships, particularly in terms of biased signaling, as well as A1AR activity and subtype selectivity. Collectively, our findings demonstrate that the allosteric moiety, particularly the 4-(trif... |
| Databáze: | OpenAIRE |
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