title: Human α1-adrenoceptor subtype selectivity of substituted homobivalent 4-aminoquinolines.
abstract: A series of ring-substituted ethyl- and heptyl-linked 4-aminoquinoline dimers were synthesized and evaluated for their affinities at the 3 human α(1)-adrenoceptor (α(1)-AR) subtypes and the human serotonin 5-HT(1A)-receptor (5-HT(1A)-R). We find that the structure-specificity profiles are different for the two series at the α(1)-AR subtypes, which suggests that homobivalent 4-aminoquinolines can be developed with α(1)-AR subtype selectivity. The 8-methyl (8-Me) ethyl-linked analogue has the highest affinity for the α(1A)-AR, 7 nM, and the greatest capacity for discriminating between α(1A)-AR and α(1B)-AR (6-fold), α(1D)-AR (68-fold), and the 5-HT(1A)-R (168-fold). α(1B)-AR selectivity was observed with the 6-methyl (6-Me) derivative of the ethyl- and heptyl-linked 4-aminoquinoline dimers and the 7-methoxy (7-OMe) derivative of the heptyl-linked analogue. These substitutions result in 4- to 80-fold selectivity for α(1B)-AR over α(1A)-AR, α(1D)-AR, and 5-HT(1A)-R. In contrast, 4-aminoquinoline dimers with selectivity for α(1D)-AR are more elusive, since none studied to date has greater affinity for the α(1D)-AR over the other two α(1)-ARs. The selectivity of the 8-Me ethyl-linked 4-aminoquinoline dimer for the α(1A)-AR, and 6-Me ethyl-linked, and the 6-Me and 7-OMe heptyl-linked 4-aminoquinoline dimers for the α(1B)-AR, makes them promising leads for drug development of α(1A)-AR or α(1B)-AR subtype selective ligands with reduced 5-HT(1A)-R affinity.
authors.affiliation: Department of Pharmacology, School of Medical Sciences, Wallace Wurth Building, UNSW Australia, Sydney, NSW 2052, Australia. Electronic address: junli.chen@unsw.edu.au.
authors.forename: Junli
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Medical Sciences, Wallace Wurth Building, UNSW Australia, Sydney, NSW 2052, Australia. Electronic address: a.campbell@unsw.edu.au.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Campbell
authors.affiliation: Department of Pharmacology, School of Medical Sciences, Wallace Wurth Building, UNSW Australia, Sydney, NSW 2052, Australia. Electronic address: k.urmi@unsw.edu.au.
authors.forename: Kaniz F
authors.initials: KF
authors.lastname: Urmi
authors.affiliation: Department of Pharmacology, School of Medical Sciences, Wallace Wurth Building, UNSW Australia, Sydney, NSW 2052, Australia. Electronic address: l.wakelin@unsw.edu.au.
authors.forename: Laurence P G
authors.initials: LP
authors.lastname: Wakelin
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: b.denny@auckland.ac.nz.
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.affiliation: Department of Pharmacology, School of Medical Sciences, Wallace Wurth Building, UNSW Australia, Sydney, NSW 2052, Australia. Electronic address: r.griffith@unsw.edu.au.
authors.forename: Renate
authors.initials: R
authors.lastname: Griffith
authors.affiliation: Department of Pharmacology, School of Medical Sciences, Wallace Wurth Building, UNSW Australia, Sydney, NSW 2052, Australia. Electronic address: angela.finch@unsw.edu.au.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Finch
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D000634:Aminoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000634:Aminoquinolines; D018340:Receptors, Adrenergic, alpha-1; D044282:Receptor, Serotonin, 5-HT1A; C001920:4-aminoquinoline
keywords: 4-Aminoquinolines; 5-HT(1A)-receptor; Affinity; Selectivity; α(1)-adrenoceptor