| 2. |
- Matricon, Pierre, et al.
(author)
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Structure-based virtual screening discovers potent and selective adenosine A1 receptor antagonists
- 2023
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 257
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Journal article (peer-reviewed)abstract
- Development of subtype-selective leads is essential in drug discovery campaigns targeting G protein-coupled receptors (GPCRs). Herein, a structure-based virtual screening approach to rationally design subtype-selective ligands was applied to the A1 and A2A adenosine receptors (A1R and A2AR). Crystal structures of these closely related subtypes revealed a non-conserved subpocket in the binding sites that could be exploited to identify A1R selective ligands. A library of 4.6 million compounds was screened computationally against both receptors using molecular docking and 20 A1R selective ligands were predicted. Of these, seven antagonized the A1R with micromolar activities and several compounds displayed slight selectivity for this subtype. Twenty-seven analogs of two discovered scaffolds were designed, resulting in antagonists with nanomolar potency and up to 76-fold A1R-selectivity. Our results show the potential of structure-based virtual screening to guide discovery and optimization of subtype-selective ligands, which could facilitate the development of safer drugs.
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| 3. |
- Sato, Masaaki, et al.
(author)
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alpha(1A)-Adrenoceptors activate mTOR signalling and glucose uptake in cardiomyocytes
- 2018
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In: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839. ; 148, s. 27-40
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Journal article (peer-reviewed)abstract
- The capacity of G protein-coupled receptors to modulate mechanistic target of rapamycin (mTOR) activity is a newly emerging paradigm with the potential to link cell surface receptors with cell survival. Cardiomyocyte viability is linked to signalling pathways involving Akt and mTOR, as well as increased glucose uptake and utilization. Our aim was to determine whether the am-adrenoceptor (AR) couples to these protective pathways, and increased glucose uptake. We characterised alpha(1A)-AR signalling in CHO-K1 cells co-expressing the human alpha(1A)-AR and GLUT4 (CHO alpha(1A)GLUT4myc) and in neonatal rat ventricular cardiomyocytes (NRVM), and measured glucose uptake, intracellular Ga2* mobilization, and phosphorylation of mTOR, Akt, 5' adenosine monophosphate-activated kinase (AMPK) and S6 ribosomal protein (S6rp). In both systems, noradrenaline and the alpha(1A)-AR selective agonist A61603 stimulated glucose uptake by parallel pathways involving mTOR and AMPK, whereas another alpha(1A)-AR agonist oxymetazoline increased glucose uptake predominantly by mTOR. All agonists promoted phosphorylation of mTOR at Ser2448 and Ser2481, indicating activation of both mTORC1 and mTORC2, but did not increase Akt phosphorylation. In CHO alpha(1A)GLUT4myc cells, siRNA directed against rictor but not raptor suppressed alpha(1A)-AR mediated glucose uptake. We have thus identified mTORC2 as a key component in glucose uptake stimulated by alpha(1A)-AR agonists. Our findings identify a novel link between the alpha(1A)-AR, mTORC2 and glucose uptake, that have been implicated separately in cardiomyocyte survival. Our studies provide an improved framework for examining the utility of alpha(1A)-AR selective agonists as tools in the treatment of cardiac dysfunction.
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