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ID: ALA5154699
Journal: Eur J Med Chem
Title: Synthesis of 8-aminomorphans with high KOR affinity.
Authors: Jonas H, Aiello D, Schepmann D, Diana P, Wünsch B.
Abstract: 2-Azabicyclo[3.3.1]nonanes (morphans) with a (3,4-dichlorophenyl)acetyl group at 2-position and a pyrrolidino moiety at 8-position were designed as conformationally restricted analogs of piperidine-based KOR agonists. The synthesis started with 4-oxopiperidine-2-carboxylic acid comprising 13 reaction steps. At first the ketone 10 was transformed into diester 7 bearing a propionate side chain. Dieckmann condensation of diester 7 to afford bicyclic enolester 14 and subsequent Krapcho deethoxycarbonylation represent the key steps of the synthesis. The enantiomeric pyrrolidines (1S,5R,8R)-5a and (1R,5S,8S)-5a were separated by chiral HPLC. The eutomer (1S,5R,8R)-5a showed high KOR affinity (Ki = 18 nM) and selectivity over MOR, DOR and σ2 receptors. It was concluded that the dihedral angle of the KOR pharmacophore N(pyrrolididine)-C-C-N(acyl) of (1S,5R,8R)-5a (68°) is close to the bioactive conformation of the flexible KOR agonist 3.
CiteXplore: 35033825