Synthesis, biological evaluation and docking studies of a novel class of sulfur-bridged diazabicyclo[3.3.1]nonanes

Gabriele Murineddu; Battistina Asproni; Paola Corona; Stefania Gessi; Stefania Merighi; Enrica Battistello; Chiara Sturaro; Girolamo Calò; Nicoletta Galeotti; Veronika Temml; Sonja Herdlinger; Daniela Schuster; Gerard A Pinna

doi:10.1016/j.bioorg.2020.104072

Synthesis, biological evaluation and docking studies of a novel class of sulfur-bridged diazabicyclo[3.3.1]nonanes

Bioorg Chem. 2020 Sep:102:104072. doi: 10.1016/j.bioorg.2020.104072. Epub 2020 Jul 6.

Authors

Affiliations

¹ Department of Chemistry and Pharmacy, University of Sassari, 07100 Sassari, Italy. Electronic address: muri@uniss.it.
² Department of Chemistry and Pharmacy, University of Sassari, 07100 Sassari, Italy.
³ Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy. Electronic address: gss@unife.it.
⁴ Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy.
⁵ Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.
⁶ Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze, 50139 Firenze, Italy.
⁷ Department of Pharmacy/Pharmacognosy, University of Innsbruck, 6020 Innsbruck, Austria.
⁸ Institute of Pharmacy/Pharmaceutical Chemistry, University of Innsbruck, 6020 Innsbruck, Austria.
⁹ Department of Pharmaceutical Chemistry, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.

PMID: 32693307
DOI: 10.1016/j.bioorg.2020.104072

Abstract

A small library of 3-thia-7,9-diazabicyclo[3.3.1]nonanes was synthesized and their opioid receptors affinity and selectivity evaluated. Among these novel sulfur-bridged compounds, the (E) 9-[3'-(3-chlorophenyl)-but-2'-en-1'-yl]-7-propionyl-3-thia-7,9-diazabicyclo[3.3.1]nonane 2i emerged as the derivative with the highest μ receptor affinity (K_i = 85 nM) and selectivity (K_i μ/δ = 58.8, K_i μ/κ > 117.6). The antinociceptive activity of 2i was also evaluated in acute thermal pain. Docking studies disclosed the specific pattern of interactions of these derivatives.

Keywords: 3-thia-7,9-diazabicyclo[3.3.1]nonanes; Antinociceptive activity; Binding affinities; Molecular docking; Opiod receptors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkanes / chemical synthesis*
Humans
Molecular Docking Simulation / methods*
Molecular Structure
Structure-Activity Relationship
Sulfur / chemistry*

Substances

Alkanes
Sulfur
nonane