title: α₁-Adrenoceptor and serotonin 5-HT(1A) receptor affinity of homobivalent 4-aminoquinoline compounds: an investigation of the effect of linker length.
abstract: α₁-adrenoceptor (α₁-AR) subtype-selective ligands lacking off-target affinity for the 5-HT(1A) receptor (5-HT(1A)-R) will provide therapeutic benefits in the treatment of urogenital conditions such as benign prostatic hyperplasia. In this study we determined the affinity of 4-aminoquinoline and eleven homobivalent 4-aminoquinoline ligands (diquinolines) with alkane linkers of 2-12 atoms (C2-C12) for α(1A), α(1B) and α(1D)-ARs and the 5-HT(1A)-R. These ligands are α(1A)-AR antagonists with nanomolar affinity for α(1A) and α(1B)-ARs. They display linker-length dependent selectivity for α(1A/B)-ARs over α(1D)-AR and the 5-HT(1A)-R. The C2 diquinoline has the highest affinity for α1A-AR (pKi 7.60±0.26) and greater than 30-fold and 600-fold selectivity for α(1A)-AR over α(1D)-AR and 5-HT(1A)-R respectively. A decrease in affinity for α₁-ARs is observed as the linker length increases, reaching a nadir at 5 (α(1A/1B)-ARs) or 6 (α(1D)-AR) atoms; after which affinity increases as the linker is lengthened, peaking at 9 (α(1A/1B/1D)-ARs) or 8 (5-HT(1A)-R) atoms. Docking studies suggest that 4-aminoquinoline and C2 bind within the orthosteric binding site, while for C9 one end is situated within the orthosteric binding pocket, while the other 4-aminoquinoline moiety interacts with the extracellular surface. The limited α(1D)-AR and 5-HT(1A)-R affinity of these compounds makes them promising leads for future drug development of α(1A)-AR selective ligands without α(1D)-AR and the 5-HT(1A)-R off-target activity.
authors.affiliation: Department of Pharmacology, School of Medical Sciences, UNSW, Sydney, NSW 2052, Australia.
authors.forename: Junli
authors.initials: J
authors.lastname: Chen
authors.forename: Ahsan K
authors.initials: AK
authors.lastname: Murad
authors.forename: Laurence P G
authors.initials: LP
authors.lastname: Wakelin
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: Renate
authors.initials: R
authors.lastname: Griffith
authors.forename: Angela M
authors.initials: AM
authors.lastname: Finch
mesh_terms: D018674:Adrenergic Antagonists / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D000634:Aminoquinolines / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D019556:COS Cells; D002458:Cell Fractionation; D002462:Cell Membrane / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D007700:Kinetics; D062105:Molecular Docking Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry* / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry* / Q000378:metabolism; D014162:Transfection
chemical_list: D018674:Adrenergic Antagonists; D000634:Aminoquinolines; D018340:Receptors, Adrenergic, alpha-1; D044282:Receptor, Serotonin, 5-HT1A