A1 Refereed original research article in a scientific journal
Transfer of SAR information from hypotensive indazole to indole derivatives acting at alpha-adrenergic receptors: In vitro and in vivo studies
Authors: Saczewski J, Hudson A, Scheinin M, Wasilewska A, Saczewski F, Rybczynska A, Ferdousi M, Laurila JM, Boblewski K, Lehmann A, Watts H, Ma DQ
Publisher: ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Publication year: 2016
Journal: European Journal of Medicinal Chemistry
Journal name in source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Journal acronym: EUR J MED CHEM
Volume: 115
First page : 406
Last page: 415
Number of pages: 10
ISSN: 0223-5234
DOI: https://doi.org/10.1016/j.ejmech.2016.03.026
Abstract
In a search for novel antihypertensive drugs we applied scaffold hopping from the previously described aradrenergic receptor antagonists, 1-[(imidazolin-2-yl)methyl]indazoles. The aim was to investigate whether the alpha-adrenergic properties of the indazole core were transferable to the indole core. The newly obtained 1-[(imidazolin-2-yl)methyl]indole analogues were screened in vitro for their binding affinities for alpha(1)- and alpha(2)-adrenoceptors, which allowed the identification of the target-based SAR transfer (T_SAR transfer) as well as structure-based SAR transfer (S_SAR transfer) events. However, when screened in vivo with use of anaesthetized male Wistar rats, the new indole ligands showed a different hemodynamic profile than expected. Instead of the immediate hypotensive effect characteristic of peripheral vasodilatator alpha(1) blockers, a biphasic effect was observed, reminiscent of clonidine-like centrally acting antihypertensive agents. This was supported by subsequent in vitro functional studies in [S-35]GTP gamma S binding assay, where the indole analogues displayed partial agonist properties at alpha(2)-adrenergic receptors. Since no correlation was found between the in vitro binding to alpha-adrenoceptors and the in vivo hemodynamic effects of the two series of indazole and indole bioisosteric compounds, in a search for new imidazoline-containing adrenergic drugs, the structure-based SAR transfer information obtained from in vitro binding studies should be treated with caution. (C) 2016 Elsevier Masson SAS. All rights reserved.
In a search for novel antihypertensive drugs we applied scaffold hopping from the previously described aradrenergic receptor antagonists, 1-[(imidazolin-2-yl)methyl]indazoles. The aim was to investigate whether the alpha-adrenergic properties of the indazole core were transferable to the indole core. The newly obtained 1-[(imidazolin-2-yl)methyl]indole analogues were screened in vitro for their binding affinities for alpha(1)- and alpha(2)-adrenoceptors, which allowed the identification of the target-based SAR transfer (T_SAR transfer) as well as structure-based SAR transfer (S_SAR transfer) events. However, when screened in vivo with use of anaesthetized male Wistar rats, the new indole ligands showed a different hemodynamic profile than expected. Instead of the immediate hypotensive effect characteristic of peripheral vasodilatator alpha(1) blockers, a biphasic effect was observed, reminiscent of clonidine-like centrally acting antihypertensive agents. This was supported by subsequent in vitro functional studies in [S-35]GTP gamma S binding assay, where the indole analogues displayed partial agonist properties at alpha(2)-adrenergic receptors. Since no correlation was found between the in vitro binding to alpha-adrenoceptors and the in vivo hemodynamic effects of the two series of indazole and indole bioisosteric compounds, in a search for new imidazoline-containing adrenergic drugs, the structure-based SAR transfer information obtained from in vitro binding studies should be treated with caution. (C) 2016 Elsevier Masson SAS. All rights reserved.
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