Human a 1 -adrenoceptor subtype selectivity of substituted homobivalent 4-aminoquinolines Junli Chen a,  , Adrian P. Campbell a,  , Kaniz F. Urmi a , Laurence P. G. Wakelin a , William A. Denny b , Renate Griffith a , Angela M. Finch a,⇑ a Department of Pharmacology, School of Medical Sciences, Wallace Wurth Building, UNSW Australia, Sydney, NSW 2052, Australia b Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand article info Article history: Received 25 May 2014 Revised 1 September 2014 Accepted 9 September 2014 Available online 16 September 2014 Keywords: a 1 -adrenoceptor 5-HT 1A -receptor 4-Aminoquinolines Affinity Selectivity abstract A series of ring-substituted ethyl- and heptyl-linked 4-aminoquinoline dimers were synthesized and evaluated for their affinities at the 3 human a 1 -adrenoceptor (a 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 a 1 -AR subtypes, which suggests that homobivalent 4-aminoquinolines can be developed with a 1 - AR subtype selectivity. The 8-methyl (8-Me) ethyl-linked analogue has the highest affinity for the a 1A -AR, 7 nM, and the greatest capacity for discriminating between a 1A -AR and a 1B -AR (6-fold), a 1D -AR (68-fold), and the 5-HT 1A -R (168-fold). a 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 a 1B -AR over a 1A -AR, a 1D -AR, and 5-HT 1A -R. In contrast, 4-aminoquinoline dimers with selectivity for a 1D -AR are more elusive, since none studied to date has greater affinity for the a 1D -AR over the other two a 1 -ARs. The selectivity of the 8-Me ethyl-linked 4-aminoquinoline dimer for the a 1A -AR, and 6-Me ethyl-linked, and the 6-Me and 7-OMe heptyl-linked 4-aminoquinoline dimers for the a 1B -AR, makes them promising leads for drug develop- ment of a 1A -AR or a 1B -AR subtype selective ligands with reduced 5-HT 1A -R affinity. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction The a 1 -adrenoceptors are G protein-coupled receptors (GPCRs) that exert their function predominantly by mediating smooth mus- cle contraction. The a 1A -AR is the predominant a 1 -AR subtype expressed in the fibro-muscular stroma of the prostate and is involved in the contraction of prostatic smooth muscle, which makes it a therapeutic target for the treatment of benign prostatic hyperplasia (BPH). 1 BPH is a common disease among aging men, causing difficulties in urination and a variety of lower urinary tract symptoms. 2 a 1 -AR antagonists are widely used to treat this condi- tion, as inhibition of a 1A -AR stimulation relaxes prostate smooth muscle, thus relieving the symptoms. 3 However, the side effect profile of current a 1 -AR antagonists used in this setting can be associated with their affinity for a 1 -AR subtypes other than a 1A -AR, or for ‘‘off-target’’ affinity for other biogenic amine recep- tors such as the serotonin 5-HT 1A -receptor (5-HT 1A -R) and dopa- mine D 3 -R. 4–7 Prazosin, terazosin and alfuzosin have a quinazoline chemical scaffold (Fig. 1), and due to their equal affin- ity for each of the a 1 -AR subtypes, have cardiovascular side effects mediated by a 1B -AR. 6 Significantly, the cardiovascular side effects of the quinazoline compounds are mostly avoided with the use of the modestly a 1A /a 1D -AR-selective antagonist tamsulosin. 8 However, tamsulosin and naftopidil, the most prevalently used a 1A -AR selective drugs for treatment of BPH, fail to discriminate between their intended target, the a 1A -AR, and the 5-HT 1A -R, 5,7 contributing in a major way to their side effect profile. 9 Thus, the discovery of new classes of a 1A -AR subtype-selective compounds http://dx.doi.org/10.1016/j.bmc.2014.09.017 0968-0896/Ó 2014 Elsevier Ltd. All rights reserved. Abbreviations: [ 3 H] prazosin, [7-methoxy- 3 H] prazosin; [ 3 H]-OH-DPAT, 8-[ 3 H- hydroxy-N,N-di-n-propyl-2-aminotetralin]; BPH, benign prostatic hyperplasia; AR, adrenoceptor; 5-HT 1A -R, serotonin receptor 1A; D 3 -R, dopamine D 3 -receptor; DMEM, Dulbecco’s modified Eagle’s medium; FBS, fetal bovine serum; DMSO, dimethylsulfoxide; PBS, phosphate buffered saline; DEAE-dextran, diethylaminoe- thane-dextran; HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; EDTA, ethylenediaminetetraacetic acid; EGTA, ethylene glycol tetraacetic acid; GPCR, G protein-coupled receptor; TM, transmembrane helix; GOLD, Genetic Optimization for Ligand Docking; DS, Discovery Studio. ⇑ Corresponding author. Tel.: +61 2 9385 1325. E-mail addresses: junli.chen@unsw.edu.au (J. Chen), a.campbell@unsw.edu. au (A.P. Campbell), k.urmi@unsw.edu.au (K.F. Urmi), l.wakelin@unsw.edu.au (L.P.G. Wakelin), b.denny@auckland.ac.nz (W.A. Denny), r.griffith@unsw.edu.au (R. Griffith), angela.finch@unsw.edu.au (A.M. Finch).   Contributed equally. Bioorganic & Medicinal Chemistry 22 (2014) 5910–5916 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc