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 alpha(1)-adrenoceptor (alpha(1)-AR) antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivity profile for alpha(1)-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 (pA(2) 10.68) and moderately selective alpha(1D)-AR antagonist and the hybrid (S)-8 is a potent (pA(2) 7.98) and highly selective alpha(1A)-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

WB4101-related compounds: New, subtype-selective alpha(1)-adrenoreceptor antagonists (or inverse agonists?) / M. Pallavicini, R. Budriesi, L. Fumagalli, P. Ioan, A. Chiarini, C. Bolchi, M.P. Ugenti, S. Colleoni, M. Gobbi, E. Valoti. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 49:24(2006), pp. 7140-7149. [10.1021/jm060358r]

WB4101-related compounds: New, subtype-selective alpha(1)-adrenoreceptor antagonists (or inverse agonists?)

M. Pallavicini
Primo
;
L. Fumagalli;C. Bolchi;S. Colleoni;E. Valoti
Ultimo
2006

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 alpha(1)-adrenoceptor (alpha(1)-AR) antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivity profile for alpha(1)-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 (pA(2) 10.68) and moderately selective alpha(1D)-AR antagonist and the hybrid (S)-8 is a potent (pA(2) 7.98) and highly selective alpha(1A)-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
Settore CHIM/08 - Chimica Farmaceutica
http://pubs.acs.org/cgi-bin/abstract.cgi/jmcmar/2006/49/i24/abs/jm060358r.html
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/25743
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