Structure-affinity studies for a novel series of homochiral naphtho and tetrahydronaphtho analogues of α 1 antagonist WB-4101

Cristiano Bolchi, Paolo Catalano, Laura Fumagalli, Marco Gobbi, Marco Pallavicini, Alessandro Pedretti, Luigi Villa, Giulio Vistoli, Ermanno Valoti

Research output: Contribution to journalArticlepeer-review

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 1a1d 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 languageEnglish
Pages (from-to)4937-4951
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume12
Issue number18
DOIs
Publication statusPublished - Sep 15 2004

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

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