Article Figures & Data
Figures
- Fig. 1.
Effect of α1-AR antagonists on the binding of [3H]-prazosin to human α1A-AR (A), α1B-AR (B), and α1D-AR (C). The membrane preparation of transfected HEK-293 cells (150 µg of protein) was incubated for 45 minutes at 30°C in 1 ml of medium containing 0.05 nM [3H]-prazosin, Tris-HCl 50 mM (pH 7.4), and 1 mM EDTA in the presence or absence of increasing concentrations of the tested compounds. The data represent the mean ± S.E.M. of three to four independent experiments performed in triplicate.
- Fig. 2.
Specific binding of [3H]-8-OH-DPAT (squares) and [3H]-p-MPPF (circles) in rat hippocampal membranes in the presence of increasing concentrations of silodosin and tamsulosin. The protein was incubated at 37°C for either 45 minutes with 0.5 nM [3H]-p-MPPF, Tris-HCl 50 mM (pH 7.4), and 1 mM GTP (low-affinity state) or 15 minutes in a solution containing 1 nM [3H]-8-OH-DPAT, 1 mM CaCl2, 1 mM MnCl2, 10 mM pargyline, and Tris-HCl 50 mM (pH 7.4; high-affinity state). Data are expressed as means ± S.E.M. of three to five individual experiments performed in triplicate.
Tables
- TABLE 1
Affinity (Ki values) and selectivity (ratios of Ki values) for binding of α1-AR antagonists to the three human α1-AR subtypes
Ki values are expressed as geometric means of [n] individual experiments. One-way ANOVA and post hoc Holm-Sidak test was performed on pKi values.
Compounds Ki (95% CI) α1A (1) Ki (95% CI) α1Dt (2) Ki (95% CI) α1B (3) Ki Ratio (2)/(1) Ki Ratio (3)/(1) nM nM nM LDT5 3.82a [3] (1.57–9.29) 4.94a [3] (19.0–9.24) 9.86 [3] (6.77–14.4) 1.29 2.90 Tamsulosin 0.36 [3] (0.11–1.17) 1.05b [3] (0.37–2.91) 1.85c [3] (1.36–5.50) 2.92 5.10 Silodosin 0.44 [3] (0.22–0.85) 11.1d [3] (5.17–23.8) 22.1d [3] (9.37–52.2) 25.2 50.2 Alfuzosin 11.4e [4] (4.31–30.4) 4.83 [4] (2.56–9.12) 2.35 [4] (1.18–4.68) 0.42 0.20 Terazosin 11.2a [4] (7.75–16.1) 6.67 [4] (2.61–17.0) 3.63 [4] (1.83–7.23) 0.59 0.32 Doxazosin 3.60 [4] (1.16–11.1 1.58 [4] (0.99–2.53) 2.16 [4] (1.40–3.32) 0.44 0.60 - TABLE 2
Affinity (Ki values) for binding to the 5-HT1A receptor (low-affinity state) and selectivity for binding to α1A-AR versus 5-HT1A receptor
Ki values are expressed as geometric means of [n] individual values calculated from competition curves using the antagonist radioligand (low-affinity state, see Materials and Methods). The ratio of these Ki values and the Ki values for α1A-AR is a measure of selectivity. Intrinsic activity at the 5-HT1A receptor was estimated by the ratio of Ki values for the low- and high-affinity state of the receptor (Noël et al., 2014).
Compounds 5-HT1A: Low Ki [n] (95% CI) Ki Ratio 5-HT1A Low/α1A-AR Ki Ratio 5-HT1A (Low/High) nM LDT5 5.96 [3] (2.64–13.5) 1.56 1.17 Tamsulosin 11.9 [5] (7.96–17.8) 33.0**** 3.91# Silodosin 4.23 [3] (1.21–14.8) 9.61** 1.20 Alfuzosin 2130 [3] (380–11,900) 186*** — Terazosin 19,890 [3] (2970–133,270) 1776**** — Doxazosin 4240 [3] (1750–10,270) 1178**** — CI, confidence interval.
↵# P < 0.01, unpaired Student’s t test on pKi values (5-HT1A low vs. 5-HT1A high); **P < 0.01; ***P < 0.001; ****P < 0.0001, unpaired Student’s t test on pKi values (5-HT1A low vs. α1A).
- TABLE 3
Affinity of tamsulosin and LDT5 for human D3 and rat striatum
D2–like receptors and selectivity for binding to the α1A-AR versus D3 receptor Ki values are expressed as geometric means of [n] individual experiments.
Compounds Ki (95% CI) D3 Ki (95% CI) D2 Ki Ratio D3/α1A nM nM Tamsulosin 15.7 [3] (3.7–37.5) 88.9 [4] (73.7–128) 43.6*** LDT5 30.7 [3] (14.7–47.5) 68.7 [5] (57.0–82.8) 8.04*** ↵*** P < 0.001, t test (pKi D3 vs. pKi α1A).
- TABLE 4
Selectivity (ratios of Ki values) for binding to α1-AR subtypes: between target subtypes and between the main target (α1A) and off-target (α1B) subtypes
Comparison between present data and data from the literature.
Compounds Ki Ratio α1Dt/α1A Ki Ratio α1B/α1A Our Data 1 2 3 4 5 6 Our Data 1 2 3 4 5 6 LDT5 1.29 — — — — — 2.90 — — — — — Tamsulosin 2.92 2.5 3.5 1.00 0.80 — 0.26 5.10 10.0 11.7 12.6 6.3 — 3.30 Silodosin 25.2 56.4 25.6 — — — 19.8 50.2 167 25.6 — — — 23.2 Alfuzosin 0.42 0.17 0.10 0.32 0.63 — 0.20 0.15 0.13 1.00 0.47 — Terazosin 0.59 0.52 0.10 — 0.50 0.15 0.32 0.49 0.10 — 0.28 0.05 Doxazosin 0.44 — 1.26 1.26 0.60 — 0.60 — 1.00 0.32 0.38 — 1, Tatemichi et al. (2006); 2, Sato et al. (2012); 3, Richardson et al. (1997); 4, Kenny et al. (1996); 5, Forray et al. (1994) (present nomenclature); 6, Ishiguro et al. (2002).
Data Supplement
- Supplemental Figure -
Selectivity of the six α1-AR antagonists for binding to the human α1A- α1B- and α1D-ARs.
- Supplemental Table -
Ki values of the five FDA-approved α1-AR antagonists for binding to the three human transfected α1-AR subtypes: overview of literature data.
- Supplemental Figure -
