Characterisation of novel alpha1-adrenoceptor ligands
type: CreativeWork
description: α1A-adrenoceptor (AR) antagonists used clinically to treat urogenital conditions, such as benign prostatic hyperplasia, have side effects due to a lack of subtype selectivity and the 5-HT1A-R off-target affinity. In this study, computer-aided drug design, structure-activity relationship, and molecular pharmacology methods were used to identify α1A-AR subtype selective compounds with reduced 5-HT1A-R off-target affinity. In silico database screening identified 2 structurally novel compounds with nanomolar affinity for the α1A-AR, and 4 compounds with selectivity for the α1A-AR over the 5-HT1A-R. Homobivalent 4-aminoquinoline compounds with increasing carbon linker lengths (C2-C12) were examined for α1A-AR selectivity. C2 and C9 provided the optimal linker length to achieve the highest affinity among this series of compounds. C2 to C6 and C12 showed selectivity for the α1A-AR over α1D-AR and the 5-HT1A-R. To improve selectivity of these compounds for α1A over α1B-AR, methyl (Me) and methoxyl (OMe) substituted analogues of C2 and C7 were produced. The substituted compound, 8-Me C2 showed selectivity for the α1A-AR over all other tested receptors, while 6-Me C2, 6-Me C7, and 7-OMe C7 were selective for the α1B-AR over all other tested receptors. Docking studies suggested that C2 bound within the orthosteric endogenous ligand binding pocket, but that C7-C11 interacted with a second allosteric site in a bitopic manner. 4-aminoquinoline, C9, C10, and C11 increased the dissociation rate of [3H] prazosin from the α1A-AR, suggesting allosteric modulation. C9 was further characterised and demonstrated to be a negative allosteric modulator of orthosteric ligands of the α1A-AR. The allosteric site was shown by docking of 4-aminoquinoline, C9, C10 and C11 to be composed of S832.61, F862.64 and E872.65, located on the extracellular part of transmembrane helix II. In further support of this region’s role in modulating orthosteric ligand affinity, F862.64 was shown to be involved in…
abstract: α1A-adrenoceptor (AR) antagonists used clinically to treat urogenital conditions, such as benign prostatic hyperplasia, have side effects due to a lack of subtype selectivity and the 5-HT1A-R off-target affinity. In this study, computer-aided drug design, structure-activity relationship, and molecular pharmacology methods were used to identify α1A-AR subtype selective compounds with reduced 5-HT1A-R off-target affinity. In silico database screening identified 2 structurally novel compounds with nanomolar affinity for the α1A-AR, and 4 compounds with selectivity for the α1A-AR over the 5-HT1A-R. Homobivalent 4-aminoquinoline compounds with increasing carbon linker lengths (C2-C12) were examined for α1A-AR selectivity. C2 and C9 provided the optimal linker length to achieve the highest affinity among this series of compounds. C2 to C6 and C12 showed selectivity for the α1A-AR over α1D-AR and the 5-HT1A-R. To improve selectivity of these compounds for α1A over α1B-AR, methyl (Me) and methoxyl (OMe) substituted analogues of C2 and C7 were produced. The substituted compound, 8-Me C2 showed selectivity for the α1A-AR over all other tested receptors, while 6-Me C2, 6-Me C7, and 7-OMe C7 were selective for the α1B-AR over all other tested receptors. Docking studies suggested that C2 bound within the orthosteric endogenous ligand binding pocket, but that C7-C11 interacted with a second allosteric site in a bitopic manner. 4-aminoquinoline, C9, C10, and C11 increased the dissociation rate of [3H] prazosin from the α1A-AR, suggesting allosteric modulation. C9 was further characterised and demonstrated to be a negative allosteric modulator of orthosteric ligands of the α1A-AR. The allosteric site was shown by docking of 4-aminoquinoline, C9, C10 and C11 to be composed of S832.61, F862.64 and E872.65, located on the extracellular part of transmembrane helix II. In further support of this region’s role in modulating orthosteric ligand affinity, F862.64 was shown to be involved in…
author: Chen, Junli
language: EN
keywords: Alpha1-adrenoceptor ligands, Urogenital conditions, Benign prostatic hyperplasia, 5-HT1A-R off-target affinity, Computer-aided drug design, Structure-activity relationship, Molecular pharmacology, Homobivalent 4-aminoquinoline compounds, Carbon linker lengths (C2-C12), Allosteric modulation, Orthosteric ligands
license: https://purl.org/coar/access_right/c_abf2
license: https://creativecommons.org/licenses/by-nc-nd/3.0/au/
date published: 2014
date modified: 2026-07-24T05:32:14Z
provider: University of New South Wales
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: UNSW, Sydney

PropertyValue
property ID: Handle
value: http://hdl.handle.net/1959.4/54080

PropertyValue
property ID: DOI
value: 10.26190/unsworks/2667