6533b859fe1ef96bd12b76eb

RESEARCH PRODUCT

Synthesis of 8-aminomorphans with high KOR affinity

Hendrik JonasDaniele AielloDirk SchepmannPatrizia DianaBernhard Wünsch

subject

Diastereoselective reductive aminationEnantiomeric excessStructure-affinity relationshipsPharmacologyPyrrolidinesReceptors Opioid kappaNOESY spectrumOrganic ChemistryMolecular ConformationStereoisomerismGeneral MedicineKOR agonistsEndo-configurationStructure-Activity RelationshipKOR pharmacophoreConformational restrictionChiral HPLCDihedral angleDrug DiscoveryCis/trans-configurationMorphan2-azabicyclo[3.3.1]nonane

description

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 (K-i = 18 nM) and selectivity over MOR, DOR and sigma(2) receptors. It was concluded that the dihedral angle of the KOR pharmacophore N(pyrrolididine)-C-C-N(acyl) of (1S,5R,8R)-5a (68 degrees) is close to the bioactive conformation of the flexible KOR agonist 3. (C) 2022 Elsevier Masson SAS. All rights reserved.

yearjournalcountryeditionlanguage
2021-12-02European Journal of Medicinal Chemistry
https://doi.org/10.1016/j.ejmech.2021.114079