Academic Journal
2-Substituted (N)-methanocarba A(3) adenosine receptor agonists : in silico, in vitro, and in vivo characterization
| العنوان: | 2-Substituted (N)-methanocarba A(3) adenosine receptor agonists : in silico, in vitro, and in vivo characterization |
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| المؤلفون: | Tosh, Dilip K., Pavan, Matteo, Cronin, Chunxia, Pottie, Eline, Wan, Tina C., Chen, Eric, Lewicki, Sarah A., Campbell, Ryan G., Gao, Zhan-Guo, Auchampach, John A., Stove, Christophe, Liang, Bruce T., Jacobson, Kenneth A. |
| المصدر: | ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE ; ISSN: 2575-9108 |
| سنة النشر: | 2024 |
| المجموعة: | Ghent University Academic Bibliography |
| مصطلحات موضوعية: | Biology and Life Sciences, Chemistry, MOLECULAR-DYNAMICS, HIGH-AFFINITY, FORCE-FIELD, DERIVATIVES, NAMODENOSON, PROTECTS, CHARMM, adenosine receptor, G protein-coupled receptor, nucleosides, G protein, arrestin, structure-activityrelationship |
| الوصف: | 2-Arylethynyl (N)-methanocarba adenosine 5 '-methylamides are selective A(3) adenosine receptor (AR) agonists containing a preestablished receptor-preferred pseudoribose conformation. Here, we compare analogues having bulky 2-substitution, either containing or lacking an ethynyl spacer between adenine and a cyclic group. 2-Aryl compounds 9-11, 13, 14, 19, 22, 23, 27, 29, 31, and 34, lacking a spacer, had human (h) A(3)AR K-i values of 2-30 nM, and others displayed lower affinity. Mouse (m) A(3)AR affinity varied, with 2-arylethynyl having a higher affinity than 2-aryl analogues (7, 8 > 3c, 3d > 3b). However, 2-aryl-4 '-truncated derivatives had greatly reduced hA(3)AR affinity, even containing affinity-enhancing N-6-dopamine-derived substituents. Molecular modeling, including molecular dynamics simulation, predicted stable poses in the canonical A(3)AR agonist binding site, but 2-aryl (ECL2 interactions) and 2-arylethynyl (TM2 interactions) substituents have different conformations and environments. In a hA(3)AR miniG alpha(i) recruitment assay, 31 (MRS8062) was (slightly) more potent compared to a beta-arrestin2 recruitment assay, both in engineered HEK293T cells, and its maximal efficacy (E-max) was much higher (165%) than reference agonist NECA's. Thus, in the 2-aryl series, A(3)AR affinity and selectivity were variable and generally reduced compared to the 2-arylethynyl series, with a greater dependence on the specific aryl group present. Selected compounds were studied in vivo in an ischemic model of peripheral artery disease (PAD). Rigidified 2-arylethynyl analogues 3a-3c were protective in this model of skeletal muscle ischemia-reperfusion injury/claudication, as previously shown only for moderately A(3)AR-selective ribosides or (N)-methanocarba derivatives. Thus, we have expanded the A(3)AR agonist SAR for (N)-methanocarba adenosines. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| Relation: | https://biblio.ugent.be/publication/01JACWQR2Z1NTC9FH2B7B5ZB0D; http://doi.org/10.1021/acsptsci.4c00223; https://biblio.ugent.be/publication/01JACWQR2Z1NTC9FH2B7B5ZB0D/file/01JACX2HPBSJ4XGJ6YDY0FDXPV |
| DOI: | 10.1021/acsptsci.4c00223 |
| الاتاحة: | https://biblio.ugent.be/publication/01JACWQR2Z1NTC9FH2B7B5ZB0D http://hdl.handle.net/1854/LU-01JACWQR2Z1NTC9FH2B7B5ZB0D https://doi.org/10.1021/acsptsci.4c00223 https://biblio.ugent.be/publication/01JACWQR2Z1NTC9FH2B7B5ZB0D/file/01JACX2HPBSJ4XGJ6YDY0FDXPV |
| Rights: | No license (in copyright) ; info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.7E646EF4 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/acsptsci.4c00223 |
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