Synthesis of 8-aminomorphans with high KOR affinity

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 reactio...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2022-02, Vol.230, p.114079-114079, Article 114079
Main Authors: Jonas, Hendrik, Aiello, Daniele, Schepmann, Dirk, Diana, Patrizia, Wünsch, Bernhard
Format: Article
Language:English
Subjects:
2-azabicyclo[3.3.1]nonane
Chiral HPLC
Cis/trans-configuration
Conformational restriction
Diastereoselective reductive amination
Dihedral angle
Enantiomeric excess
Endo-configuration
KOR agonists
KOR pharmacophore
Molecular Conformation
Morphan
NOESY spectrum
Pyrrolidines
Receptors, Opioid, kappa
Stereoisomerism
Structure-Activity Relationship
Structure-affinity relationships
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Summary: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. [Display omitted] •Conformational restriction of potent KOR agonists resulted in 8-aminomorphans.•Dieckmann condensation led to the bicyclic system.•Reductive amination provided stereoselectively the endo-configured aminomorphans.•Enantiomers were separated by chiral HPLC.•High KOR affinity (Ki = 18 nM) was observed for the pyrrolidine derivative.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2021.114079