0000000001009759
AUTHOR
Kirstin Lehmkuhl
Synthesis and pharmacological evaluation of enantiomerically pure endo-configured KOR agonists with 2-azabicyclo[3.2.1]octane scaffold
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 …
Novel σ1 antagonists designed for tumor therapy: Structure – activity relationships of aminoethyl substituted cyclohexanes
Abstract Depending on the substitution pattern and stereochemistry, 1,3-dioxanes 1 with an aminoethyl moiety in 4-position represent potent σ1 receptor antagonists. In order to increase the stability, a cyclohexane ring first replaced the acetalic 1, 3-dioxane ring of 1. A large set of aminoethyl substituted cyclohexane derivatives was prepared in a six-step synthesis. All enantiomers and diastereomers were separated by chiral HPLC at the stage of the primary alcohol 7, and their absolute configuration was determined by CD spectroscopy. Neither the relative nor the absolute configuration had a large impact on the σ1 affinity. The highest σ1 affinity was found for cis-configured benzylamines…