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.

Jonas, H., Aiello, D., Schepmann, D., Diana, P., Wünsch, B. (2022). Synthesis of 8-aminomorphans with high KOR affinity. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 230, 1-11 [10.1016/j.ejmech.2021.114079].

Synthesis of 8-aminomorphans with high KOR affinity

Jonas, Hendrik
Primo
;
Aiello, Daniele
Secondo
;
Diana, Patrizia
Penultimo
;
2022-02-15

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 (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.
15-feb-2022
Jonas, H., Aiello, D., Schepmann, D., Diana, P., Wünsch, B. (2022). Synthesis of 8-aminomorphans with high KOR affinity. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 230, 1-11 [10.1016/j.ejmech.2021.114079].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/572601
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