¦Á₁-Adrenoceptor and serotonin 5-HT_1A receptor affinity of homobivalent 4-aminoquinoline compounds: An investigation of the effect of linker length

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• 作者：Junli Chen^a ; ^{junli.chen@unsw.edu.au} ; Ahsan K. Murad^a ; ^{m.a.murad@unsw.edu.au} ; Laurence P.G. Wakelin^a ; ^{l.wakelin@unsw.edu.au} ; William A. Denny^b ; ^{b.denny@auckland.ac.nz} ; Renate Griffith^a ; ^{r.griffith@unsw.edu.au} ; Angela M. Finch^a ; ^{a.finch@unsw.edu.au}
• 关键词：GPCR ; ¦Á1-Adrenergic receptor ; Subtype selectivity ; Serotonin receptor ; Diquinoline ; Linker length
• 刊名：Biochemical Pharmacology
• 出版年：2013
• 出版时间：15 May, 2013
• 年：2013
• 卷：85
• 期：10
• 页码：1534-1541
• 全文大小：1088 K

文摘

¦Á₁-adrenoceptor (¦Á₁-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 ¦Á_1A, ¦Á_1B and ¦Á_1D -ARs and the 5-HT_1A-R. These ligands are ¦Á_1A-AR antagonists with nanomolar affinity for ¦Á_1A and ¦Á_1B -ARs. They display linker-length dependent selectivity for ¦Á_1A/B -ARs over ¦Á_1D-AR and the 5-HT_1A-R. The C2 diquinoline has the highest affinity for ¦Á_1A-AR (pK_i 7.60 ¡À 0.26) and greater than 30-fold and 600-fold selectivity for ¦Á_1A-AR over ¦Á_1D-AR and 5-HT_1A-R respectively. A decrease in affinity for ¦Á₁-ARs is observed as the linker length increases, reaching a nadir at 5 (¦Á_1A/1B-ARs) or 6 (¦Á_1D-AR) atoms; after which affinity increases as the linker is lengthened, peaking at 9 (¦Á_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 ¦Á_1D-AR and 5-HT_1A-R affinity of these compounds makes them promising leads for future drug development of ¦Á_1A-AR selective ligands without ¦Á_1D-AR and the 5-HT_1A-R off-target activity.