WB4101-Related Compounds:  New, Subtype-Selective α₁-Adrenoreceptor Antagonists (or Inverse Agonists?)

Abstract

Our previous structure-affinity relationship study had considered the enantiomers of the naphthodioxane, tetrahydronaphthodioxane, and 2-methoxy-1-naphthoxy analogues (compounds 1, 3, and 2, respectively) of 2-(2,6-dimethoxyphenoxyethylaminomethyl)-1,4-benzodioxane, the well-known alpha1-adrenoceptor (alpha1-AR) antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivity profile for alpha1-AR subtypes and 5-HT1A receptor. Here, we extend investigations to antagonist activity enclosing new enantiomeric pairs, namely those of the methoxytetrahydronaphthoxy and methoxybiphenyloxy WB4101 analogues (4 and 5-7, respectively) and of a double-modified WB4101 derivative (8) resulting from hybridization between 2 and 3. We found that (S)-2 is a very potent (pA2 10.68) and moderately selective alpha1D-AR antagonist and the hybrid (S)-8 is a potent (pA2 7.98) and highly selective alpha1A-AR antagonist. Both of these compounds and (S)-WB4101 seem to act as inverse agonists in a vascular model. The results, which generally validate the logic we followed in designing these eight compounds, are acceptably rationalized by comparative SAR analysis of binding and functional affinities.

Synthesis and Blocking Activities of Isoindolinone- and Isobenzofuranone-Containing Phenoxylalkylamines as Potent .ALPHA.1-Adrenoceptor Antagonists

“…Given the fact that compounds 1 and 7 showed comparable activity with DDPH, bulkiness may be the predominant factor for the potency of compounds 1-12. In addition, introducing at the aromatic group B of bulky groups, for example, 3,4-dihydro-2H-benzo[e] [1,2]thiazine-1,1-dioxide, led to a dramatic decrease in the activity, 23) suggesting that bulkiness at the aromatic group A may be preferable, which is in agreement with our structure-activity correlation study. 12) Secondly, isoindolinone-containing compounds 1-6 did not consistently show higher blocking activities than isobenzofuranone-conjugated compounds 7-12, and vice versa.…”

“…After filtered, the obtained solid was washed with ethyl acetate and re-crystallized with a mixture of methanol-ethyl acetate (2/5 by volume) to give 1 (0.2 g, 34%) as a white hydrochloride salt having mp 196. Determination of pA 2 Value of Each Compound The blocking activity (pA 2 ) of each compound was measured by using the methods similar to those described previously. [23][24][25][26] Specifically, a male Sprague-Dawley rat (300-350 g) was killed by cervical dislocation and its anococcygeus smooth muscles were isolated.…”

“…[1][2][3] These efforts have been prompted primarily by their wide applications, for example, in the treatment of benign prostatic hyperplasia (BPH) 4) and high blood pressure. 5) To date, several types of a 1 -AR antagonists, such as prazosin, 6) terazosin, 7) tamsuolosin, 8) have been developed as effective antihypertensive and BPH therapeutic drugs.…”

A selective alpha1D-adrenoreceptor antagonist inhibits human prostate cancer cell proliferation and motility “in vitro”

“…The multifaceted efficacy of the compound also in the absence of a stimulating effect by catecholamines suggests that A175 might behave as an inverse agonist of a receptor endowed with constitutive activity [3]; this action appears to be different from the neutral antagonist behavior we previously observed for this molecule in other functional tests [34]. As alpha1D-ARs display a prevalent intracellular localization [3,11,42,52], we wondered whether the effect of A175 might either the formation of homo/heterodimers [54], or the crosstalk with other membrane proteins, such as calcium channels [16].…”

“…On the basis that 1-not all the alpha1D-AR antagonists can suppress PC growth and 2-not all the antiproliferative alpha1D-AR antagonists have a receptor-mediated action, we undertook the present study on A175, a new potent and selective alpha1D-AR antagonist we recently discovered through a long series of modifications of the well-known potent but not subtype selective alpha1-AR antagonist 2-(2,6-dimethoxyphenoxyethylaminomethyl)-1,4-benzodioxane ((S)-WB4101 [32][33][34][35][36][37]). The chemical structures of the two compounds are shown in the box below.…”