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 α1-adrenoceptor (α1-AR) antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivity profile for α1-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 α1D-AR antagonist and the hybrid (S)-8 is a potent (pA2 7.98) and highly selective α1A-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.
| Original language | English |
|---|---|
| Pages (from-to) | 7140-7149 |
| Number of pages | 10 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 49 |
| Issue number | 24 |
| DOIs | |
| Publication status | Published - Nov 30 2006 |
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ASJC Scopus subject areas
- Organic Chemistry
Cite this
WB4101-related compounds : New, subtype-selective α1- adrenoreceptor antagonists (or inverse agonists?). / Pallavicini, Marco; Budriesi, Roberta; Fumagalli, Laura; Ioan, Pierfranco; Chiarini, Alberto; Bolchi, Cristiano; Ugenti, Maria Paola; Colleoni, Simona; Gobbi, Marco; Valoti, Ermanno.
In: Journal of Medicinal Chemistry, Vol. 49, No. 24, 30.11.2006, p. 7140-7149.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - WB4101-related compounds
T2 - New, subtype-selective α1- adrenoreceptor antagonists (or inverse agonists?)
AU - Pallavicini, Marco
AU - Budriesi, Roberta
AU - Fumagalli, Laura
AU - Ioan, Pierfranco
AU - Chiarini, Alberto
AU - Bolchi, Cristiano
AU - Ugenti, Maria Paola
AU - Colleoni, Simona
AU - Gobbi, Marco
AU - Valoti, Ermanno
PY - 2006/11/30
Y1 - 2006/11/30
N2 - 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 α1-adrenoceptor (α1-AR) antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivity profile for α1-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 α1D-AR antagonist and the hybrid (S)-8 is a potent (pA2 7.98) and highly selective α1A-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.
AB - 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 α1-adrenoceptor (α1-AR) antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivity profile for α1-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 α1D-AR antagonist and the hybrid (S)-8 is a potent (pA2 7.98) and highly selective α1A-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.
UR - http://www.scopus.com/inward/record.url?scp=33845349565&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33845349565&partnerID=8YFLogxK
U2 - 10.1021/jm060358r
DO - 10.1021/jm060358r
M3 - Article
C2 - 17125266
AN - SCOPUS:33845349565
VL - 49
SP - 7140
EP - 7149
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 24
ER -