α1-Adrenoceptor and serotonin 5-HT1A receptor affinity of homobivalent 4-aminoquinoline compounds: An investigation of the effect of linker length

α1-adrenoceptor (α1-AR) subtype-selective ligands lacking off-target affinity for the 5-HT1A receptor (5-HT1A-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 α1A, α1B and α1D -ARs and the 5-HT1A-R. These ligands are α1A-AR antagonists with nanomolar affinity for α1A and α1B -ARs. They display linker-length dependent selectivity for α1A/B -ARs over α1D-AR and the 5-HT1A-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 α1A-AR over α1D-AR and 5-HT1A-R respectively. A decrease in affinity for α1-ARs is observed as the linker length increases, reaching a nadir at 5 (α1A/1B-ARs) or 6 (α1D-AR) atoms; after which affinity increases as the linker is lengthened, peaking at 9 (α1A/1B/1D-ARs) or 8 (5-HT1A-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 α1D-AR and 5-HT1A-R affinity of these compounds makes them promising leads for future drug development of α1A-AR selective ligands without α1D-AR and the 5-HT1A-R off-target activity.

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