title: Transfer of SAR information from hypotensive indazole to indole derivatives acting at α-adrenergic receptors: In vitro and in vivo studies.
abstract: In a search for novel antihypertensive drugs we applied scaffold hopping from the previously described α1-adrenergic receptor antagonists, 1-[(imidazolin-2-yl)methyl]indazoles. The aim was to investigate whether the α-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 α1-and α2-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 α1 blockers, a biphasic effect was observed, reminiscent of clonidine-like centrally acting antihypertensive agents. This was supported by subsequent in vitro functional studies in [(35)S]GTPγS binding assay, where the indole analogues displayed partial agonist properties at α2-adrenergic receptors. Since no correlation was found between the in vitro binding to α-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.
authors.affiliation: Department of Organic Chemistry, Medical University of Gdańsk, 80-416, Gdańsk, Poland. Electronic address: js@gumed.edu.pl.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Sączewski
authors.affiliation: Department of Pharmacology, 9-47 Medical Sciences Building, University of Alberta, Edmonton, T6G 2H7, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: Hudson
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, and Turku University Hospital, FI-20014 Turku, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
authors.affiliation: Department of Chemical Technology of Drugs, Medical University of Gdańsk, 80-416, Gdańsk, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wasilewska
authors.affiliation: Department of Chemical Technology of Drugs, Medical University of Gdańsk, 80-416, Gdańsk, Poland.
authors.forename: Franciszek
authors.initials: F
authors.lastname: Sączewski
authors.affiliation: Department of Pathophysiology, Medical University of Gdansk, Poland.
authors.forename: Apolonia
authors.initials: A
authors.lastname: Rybczyńska
authors.affiliation: Department of Pharmacology, 9-47 Medical Sciences Building, University of Alberta, Edmonton, T6G 2H7, Canada.
authors.forename: Mehnaz
authors.initials: M
authors.lastname: Ferdousi
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, and Turku University Hospital, FI-20014 Turku, Finland.
authors.forename: Jonne M
authors.initials: JM
authors.lastname: Laurila
authors.affiliation: Department of Pathophysiology, Medical University of Gdansk, Poland.
authors.forename: Konrad
authors.initials: K
authors.lastname: Boblewski
authors.affiliation: Department of Pathophysiology, Medical University of Gdansk, Poland.
authors.forename: Artur
authors.initials: A
authors.lastname: Lehmann
authors.affiliation: Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors.forename: Helena
authors.initials: H
authors.lastname: Watts
authors.affiliation: Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors.forename: Daqing
authors.initials: D
authors.lastname: Ma
mesh_terms: D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000959:Antihypertensive Agents; D007191:Indazoles; D007211:Indoles
keywords: Imidazolines; Indazoles; Indoles; SAR-transfer events; α-adrenergic agents