Jump to main content
Jump to site search

Issue 31, 2017
Previous Article Next Article

Stereoselective synthesis of conformationally restricted KOR agonists based on the 2,5-diazabicyclo[2.2.2]octane scaffold

Author affiliations

Abstract

It has been postulated that the KOR affinity depends on the dihedral angle of the ethylenediamine pharmacophore. Herein, 2,5-diazabicyclooctanes bearing a pyrrolidino moiety in the 7-position were envisaged to study KOR agonists with a conformationally rigid ethylenediamine pharmacophore and thus a defined N(pyrrolidine)–C7–C1–N2 dihedral angle. The first approach with an intramolecular addition at the chiral sulfinylimines 9 failed to give bicyclic products. The key step in the second approach was a Dieckmann analogous cyclization providing mixed methyl silyl ketals 11a–e as key intermediates. The highest KOR affinity was found for the 2,5-dibenzyl substituted derivatives (S,R,S)-16a (Ki = 31 nM) and (R,S,R)-16a (Ki = 74 nM) with the pyrrolidine ring oriented towards N-5. The high KOR affinity of (S,R,S)-16a is unexpected, since the KOR pharmacophoric ethylenediamine system adopts a dihedral angle of about 160°, which is quite different from the angle of the energetically most favored conformer of the flexible and potent KOR agonist 2. (S,R,S)-16a represents a KOR agonist with moderate selectivity over MOR (8-fold) and DOR (5-fold), but high selectivity over both σ receptor subtypes. In the [35S]GTPγS assay (S,R,S)-16a reacted as a full KOR agonist with an EC50 value of 240 nM.

Graphical abstract: Stereoselective synthesis of conformationally restricted KOR agonists based on the 2,5-diazabicyclo[2.2.2]octane scaffold

Back to tab navigation

Supplementary files

Publication details

The article was received on 23 Jun 2017, accepted on 18 Jul 2017 and first published on 18 Jul 2017


Article type: Paper
DOI: 10.1039/C7OB01530E
Org. Biomol. Chem., 2017,15, 6520-6540

  •   Request permissions

    Stereoselective synthesis of conformationally restricted KOR agonists based on the 2,5-diazabicyclo[2.2.2]octane scaffold

    C. Wittig, D. Schepmann, M. Soeberdt, C. G. Daniliuc and B. Wünsch, Org. Biomol. Chem., 2017, 15, 6520
    DOI: 10.1039/C7OB01530E

Search articles by author

Spotlight

Advertisements