Abstract
A number of enantiomeric pairs of naphthodioxane, tetrahydronaphthodioxane and naphthoxy analogues of WB-4101 (1) were designed and synthesized in order to improve the selectivity profile of the parent compound, hopefully in favour of the α 1a-AR with respect to the other two α 1 subtypes and the 5-HT 1A receptor. The new compounds 2-8 and, in addition, the two enantiomers of 1 were tested in binding assays on the α 1a-AR, α 1b-AR, α 1d-AR, and the 5-HT 1A receptor. Two of them, namely the naphtho- and tetrahydronaphthodioxane derivatives (S)-2 and (S)-3, showed lower, but significantly more specific α 1a affinity than (S)-1, while the two enantiomers of the 2-methoxy-1-naphthoxy analogue 6 maintained most of the very high α 1a affinity of (S)-1 and its α 1a versus α 1b selectivity slightly increasing the α 1a/α 1d and α 1a/5HT 1A affinity ratios. The SAR data were evaluated in the light of known α 1 subtype pharmacophores and of the α 1a-AR binding mode of WB-4101 resultant from literature mutagenesis studies disclosing some interesting consonances with these models.
| Original language | English |
|---|---|
| Pages (from-to) | 4937-4951 |
| Number of pages | 15 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 12 |
| Issue number | 18 |
| DOIs | |
| Publication status | Published - Sep 15 2004 |
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Keywords
- α -Adrenergic receptor subtypes
- α -Antagonist
- 5-HT serotoninergic receptor
- Binding affinity
- WB-4101
- WB-4101 analogues
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Organic Chemistry
- Drug Discovery
- Pharmaceutical Science
Cite this
Structure-affinity studies for a novel series of homochiral naphtho and tetrahydronaphtho analogues of α 1 antagonist WB-4101. / Bolchi, Cristiano; Catalano, Paolo; Fumagalli, Laura; Gobbi, Marco; Pallavicini, Marco; Pedretti, Alessandro; Villa, Luigi; Vistoli, Giulio; Valoti, Ermanno.
In: Bioorganic and Medicinal Chemistry, Vol. 12, No. 18, 15.09.2004, p. 4937-4951.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Structure-affinity studies for a novel series of homochiral naphtho and tetrahydronaphtho analogues of α 1 antagonist WB-4101
AU - Bolchi, Cristiano
AU - Catalano, Paolo
AU - Fumagalli, Laura
AU - Gobbi, Marco
AU - Pallavicini, Marco
AU - Pedretti, Alessandro
AU - Villa, Luigi
AU - Vistoli, Giulio
AU - Valoti, Ermanno
PY - 2004/9/15
Y1 - 2004/9/15
N2 - A number of enantiomeric pairs of naphthodioxane, tetrahydronaphthodioxane and naphthoxy analogues of WB-4101 (1) were designed and synthesized in order to improve the selectivity profile of the parent compound, hopefully in favour of the α 1a-AR with respect to the other two α 1 subtypes and the 5-HT 1A receptor. The new compounds 2-8 and, in addition, the two enantiomers of 1 were tested in binding assays on the α 1a-AR, α 1b-AR, α 1d-AR, and the 5-HT 1A receptor. Two of them, namely the naphtho- and tetrahydronaphthodioxane derivatives (S)-2 and (S)-3, showed lower, but significantly more specific α 1a affinity than (S)-1, while the two enantiomers of the 2-methoxy-1-naphthoxy analogue 6 maintained most of the very high α 1a affinity of (S)-1 and its α 1a versus α 1b selectivity slightly increasing the α 1a/α 1d and α 1a/5HT 1A affinity ratios. The SAR data were evaluated in the light of known α 1 subtype pharmacophores and of the α 1a-AR binding mode of WB-4101 resultant from literature mutagenesis studies disclosing some interesting consonances with these models.
AB - A number of enantiomeric pairs of naphthodioxane, tetrahydronaphthodioxane and naphthoxy analogues of WB-4101 (1) were designed and synthesized in order to improve the selectivity profile of the parent compound, hopefully in favour of the α 1a-AR with respect to the other two α 1 subtypes and the 5-HT 1A receptor. The new compounds 2-8 and, in addition, the two enantiomers of 1 were tested in binding assays on the α 1a-AR, α 1b-AR, α 1d-AR, and the 5-HT 1A receptor. Two of them, namely the naphtho- and tetrahydronaphthodioxane derivatives (S)-2 and (S)-3, showed lower, but significantly more specific α 1a affinity than (S)-1, while the two enantiomers of the 2-methoxy-1-naphthoxy analogue 6 maintained most of the very high α 1a affinity of (S)-1 and its α 1a versus α 1b selectivity slightly increasing the α 1a/α 1d and α 1a/5HT 1A affinity ratios. The SAR data were evaluated in the light of known α 1 subtype pharmacophores and of the α 1a-AR binding mode of WB-4101 resultant from literature mutagenesis studies disclosing some interesting consonances with these models.
KW - α -Adrenergic receptor subtypes
KW - α -Antagonist
KW - 5-HT serotoninergic receptor
KW - Binding affinity
KW - WB-4101
KW - WB-4101 analogues
UR - http://www.scopus.com/inward/record.url?scp=4444222928&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4444222928&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2004.06.040
DO - 10.1016/j.bmc.2004.06.040
M3 - Article
C2 - 15336273
AN - SCOPUS:4444222928
VL - 12
SP - 4937
EP - 4951
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 18
ER -