α_1-Adrenoceptor Subtype Selectivity and Organ Specificity of Silodosin (KMD-3213)

Abstract

The selectivity of silodosin (KMD − 3213)， an antagonist of or1− adrenoceptor (AR) ， to the subtypes (α 且 A − ， α IB − and α ID − ARs)was examined by a receptor − binding study and a functional pharmacological study ， and we compared its sub − type − selectivity With those of other α 1 − AR antagonjsts ． In the receptor − binding study ， a replacement experiment using ［ 3H ］ − prazosin was conducted using the membrane fraction of mouse − derived LM (tk −)cells in which each of three hu − man ai − AR subtypes was expressed ． ln the functional pharmacological study ， the following isolated tissues were used as representative organs with high distribution densities of α 1 − AR subtypes (α 1A − AR ：rabbit prostate ， urethra and bladder trigone ；α 1B − AR ：rat spleen ；α 1D − AR ： rat thoracic aorta) ． Using the Magnus methQd ， we studied the inhibitory effect of silodosin on noradrenalille − induced contraction ， and compared it with those of tamsulosin hydrochloride ， naftopidil and prazosin hydrochloride ． Silodosin showed higher selectivity for the α 1A − AR subtype than tamsulosin hydrochloride ， naftopidil or prazosin hydrochloride(aMnity was highest for tamsulosin hydrochloride ， followed by silodosin ， prazosin hydrochloride and naftopidil in that order)． Silodosin strong antagonized noradrenaline − induced contractions in rabbit lower urinary tract tissues (including prostate ， urethra and bladder trigon ¢ ， with pA20r pKb values of 9 ． 60， 8． 71 and 9． 35， respectively) 。 On the other hand ， the pA2 values for antagonism of noradrenaline ． induced contractions in rat iso − 1ated spleen and rat isolated thoracic aorta were 7 ． 15and 7 ， 88 ， respectively ． Seiectivity for lower urinary tract was higher for silodosin than for the other α 1 − AR antagonists ． Our data suggest that silodosin has a high selectivity for the α 1A − AR subtype and for the lower urinary tract ．

Chiral recognition of doxazosin enantiomers in 3 targets for therapy as well as adverse drug reactions in animal experiments

“…␣ 1D -Adrenoceptor predominantly mediates NA-induced contraction of the rat thoracic aorta (Marucci et al 2005). In contrast to the rat thoracic aorta, ␣ 1A -adrenoceptor is the predominant subtype expressed in the rabbit prostate, which is responsible for the NA-induced contractile responses (Tatemichi et al 2006). In the isolated rabbit prostate preparations used in this study, we further found that the concentration-contraction curves for PHE were inhibited by (-)DOX, (ϩ)DOX, and (Ϯ)DOX in a competitive manner, and there were no signifi- -29.4Ϯ7.72)** Note: *, P Ͻ 0.05 and **, P Ͻ0.01 compared with the solvent control; # , P Ͻ 0.05 and ## , P Ͻ 0.01 compared with preparation before drug administration.…”

“…Here, we speculate that a chiral carbon atom in the molecular structure of doxazosin does not affect its activity at the therapeutic target of ␣ 1A -adrenoceptors in the prostate, but significantly changes its blocking activity against vasculature ␣ 1A -adrenoceptors and its inotropic effects in the heart tissues via an ␣ 1 -adrenoceptorindependent mechanism. Therefore, the first step of this study was to determine the pA 2 (or pK B ) values for (ϩ)DOX and (-)DOX using 2 classical and widely used in-vitro models for ␣ 1 -adrenoceptor subtypes, which is the rabbit prostate preparation (Tatemichi et al 2006) for ␣ 1A -adrenoceptors, and the rat thoracic aorta preparation (Marucci et al 2005) for ␣ 1D -adrenoceptors. Then, the inotropic and chronotropic effects of high concentrations of (ϩ)DOX and (-)DOX were analyzed in isolated heart preparations.…”

Discovery of LASSBio-772, a 1,3-benzodioxole N-phenylpiperazine derivative with potent alpha 1A/D-Adrenergic receptor blocking properties

“…2), used clinically as a second generation therapeutic agent, has been reported to present a better uroselectivity profile due to its relatively higher affinity for alpha 1A and 1D subtypes [17]. However, its selectivity is modest and therefore is directly dependent on the therapeutic dosage (0.4 mg/day) ensuring the right balance between efficacy and safety [17e19].…”

Non‑Hormonal treatment of BPH/BOO

“…[29] In vitro studies showed that silodosin's alpha-1a: Alpha-1b binding ratio is in the order of 160:1. [29] Clinically, this has resulted in rapid and sustained efficacy, increased flow rates as well as improvements in quality of life scores, which are broadly comparable to tamsulosin.…”

“…[29] In vitro studies showed that silodosin's alpha-1a: Alpha-1b binding ratio is in the order of 160:1. [29] Clinically, this has resulted in rapid and sustained efficacy, increased flow rates as well as improvements in quality of life scores, which are broadly comparable to tamsulosin. [3031] Silodosin was found to have minimal risk of cardiovascular effects although it did have a greater risk of ejaculatory dysfunction than tamsulosin in direct comparisons, 14.2 to 22.3% versus 1.6-2.1%, respectively.…”