Synthesis and pharmacological evaluation of enantiomerically pure endo-configured KOR agonists with 2-azabicyclo[3.2.1]octane scaffold
| Autor: | Kirstin Lehmkuhl, Patrizia Diana, Hendrik Jonas, Jens Köhler, Dirk Schepmann, Daniele Aiello, Bernhard Wünsch, Bastian Frehland |
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| Přispěvatelé: | Hendrik Jona, Daniele Aiello, Bastian Frehland, Kirstin Lehmkuhl, Dirk Schepmann, Jens Köhler, Patrizia Diana, Bernhard Wünsch |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
Ketone Bicyclic molecule Stereochemistry Organic Chemistry KOR agonist opioid receptor Biochemistry Reductive amination Pyrrolidine Chiral column chromatography chemistry.chemical_compound chemistry Chiral pool synthesis 2-azabicyclo[3.2.1]octane Moiety Physical and Theoretical Chemistry Enantiomer |
| Popis: | Conformationally restricted bicyclic KOR agonists 10 with an endo configured amino moiety were synthesized to analyze the bioactive conformation of conformationally flexible KOR agonists such as 2-5. A seven-step, chiral pool synthesis starting with (S)-configured 4-oxopiperidine-2-carboxylate 13 was developed. cis and trans configured diesters 12 were obtained in a 3:1 ratio via hydrogenation of the α,β unsaturated ester 14. After establishment of the bicyclic scaffold, a diastereoselective reductive amination of ketone 11 provided exclusively the endo configured bicyclic amines 10a,b. The 3:1 mixtures of enantiomers were separated by chiral HPLC, respectively, leading to enantiomerically pure KOR agonists (1S,5S,7R)-10a,b and (1R,5R,7S)-10a,b (ent 10a,b). The KOR affinity was determined in receptor binding studies with the radioligand [3H]U-69,593. The high KOR affinity of endo-configured amines 10a (Ki = 7 nM) and 10b (Ki = 13 nM) indicates that the dihedral angle of the KOR pharmacophoric element N(pyrrolidine)-C-C-N(phenylacetyl) of 42° is close to the bioactive conformation of more flexible KOR agonists. It should be noted that changing the configuration of potent and selective KOR agonists 10a and 10b led to potent and selective 1 ligands (e.g. ent-10a Ki(1) = 10 nM). |
| Databáze: | OpenAIRE |
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