Pharmacological characterization of high-affinity σ1 receptor ligands with spirocyclic thienopyran and thienofuran scaffold
Abstract Objectives In this study, the pharmacological properties of six spirocyclic piperidines 1–6 showing very high σ1 receptor affinity (Ki = 0.2–16 nm) were investigated. Methods In vitro receptor binding studies, retinal ganglion assay and in vivo capsaicin assay were used to determine the affinity, selectivity and activity. Influence on human tumour cell growth (cell lines A427, LCLC-103H, 5637 and DAN-G) was determined in different assays. The effect on the ergosterol and cholesterol biosynthesis was determined by GLC/MS analysis. Key findings Receptor binding studies demonstrated high selectivity for the σ1 receptor. The increased Ca2+ influx mediated by 2 and the analgesic activit…
Synthesis and Structure-Affinity Relationships of Spirocyclic Benzopyrans with Exocyclic Amino Moiety
σ1 and/or σ2 receptors play a crucial role in pathological conditions such as pain, neurodegenerative disorders, and cancer. A set of spirocyclic cyclohexanes with diverse O-heterocycles and amino moieties (general structure III) was prepared and pharmacologically evaluated. In structure-activity relationships studies, the σ1 receptor affinity and σ1:σ2 selectivity were correlated with the stereochemistry, the kind and substitution pattern of the O-heterocycle, and the substituents at the exocyclic amino moiety. cis-configured 2-benzopyran cis-11b bearing a methoxy group and a tertiary cyclohexylmethylamino moiety showed the highest σ1 affinity ( Ki = 1.9 nM) of this series of compounds. In…
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…
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 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…