From pyrrolidinyl-benzodioxane to pyrrolidinyl-pyridodioxanes, or from unselective antagonism to selective partial agonism at α4β2 nicotinic acetylcholine receptor

Cristiano Bolchi, Francesco Bavo, Cecilia Gotti, Laura Fumagalli, Francesca Fasoli, Matteo Binda, Vanessa Mucchietto, Miriam Sciaccaluga, Simona Plutino, Sergio Fucile, Marco Pallavicini

Research output: Contribution to journalArticlepeer-review

Abstract

Each of the four aromatic –CH= of (S,R)-2-pyrrolidinyl-1,4-benzodioxane [(S,R)-6] and of its epimer at the dioxane stereocenter (S,S)-6, previously reported as α4β2 nAChR ligands, was replaced with nitrogen. The resulting four diastereoisomeric pairs of pyrrolidinyl-pyridodioxanes were studied for the nicotinic affinity and activity at α4β2, α3β4 and α7 nAChR subtypes and compared to their common carbaisostere. It turned out that such isosteric substitutions are highly detrimental, but with the important exception of the S,R stereoisomer of the pyrrolidinyl-pyridodioxane with the pyridine nitrogen adjacent to the dioxane and seven atoms distant from the pyrrolidine nitrogen. Indeed, this stereo/regioisomer not only maintained the α4β2 affinity of [(S,R)-6], but also greatly improved in selectivity over the α3β4 and α7 subtypes and, most importantly, exhibited a highly selective α4β2 partial agonism. The finding that [(S,R)-6] is, instead, an unselective α4β2 antagonist indicates that the benzodioxane substructure confers affinity for the α4β2 nAChR binding site, but activation of this receptor subtype needs benzodioxane functionalization under strict steric requirements, such as the previously reported 7-OH substitution or the present isosteric modification.

Original languageEnglish
Pages (from-to)1132-1144
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume125
DOIs
Publication statusPublished - Jan 5 2017

Keywords

  • Antagonism
  • Benzodioxane
  • Partial agonism
  • Pyridodioxane
  • α3β4 nAChR
  • α4β2 nAChR

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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