Synthesis and σ receptor affinity of regioisomeric spirocyclic furopyridines
| Autor: | Bernhard Wünsch, Kengo Miyata, Dirk Schepmann |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Pyridines
Stereochemistry Guinea Pigs chemistry.chemical_element Chemistry Techniques Synthetic Ring (chemistry) σ1 receptor Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Pyridine Structural isomer Animals Receptors sigma Spiro Compounds Benzofuran Receptor Pharmacology Bromine Chemistry Organic Chemistry Hydrogen Bonding Stereoisomerism General Medicine Rats Radioligand binding Cyclization Protein Binding |
| Zdroj: | European Journal of Medicinal Chemistry. 83:709-716 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2014.06.073 |
| Popis: | In order to investigate systematically the effect of the position of the pyridine N-atom on the σ1 receptor affinity four regioisomeric furopyridines 2a–d were synthesized and pharmacologically evaluated. The key steps of the synthesis comprise bromine/lithium exchange at regioisomeric bromopyridinecarbaldehyde acetals 7a–d, subsequent addition to 1-benzylpiperidin-4-one and cyclization. The regioisomeric acetals 7a–d were obtained either by o-metalation of bromopyridines 5b and 5c or by oxidation of bromopicolines 3a and 3d. In radioligand binding studies the regioisomeric furopyridines 2a–d showed 7- to 12-fold lower σ1 affinity than the benzofuran analog 1. The reduced σ1 affinity of the furopyridines 2a–d is explained with the reduced electron density of the pyridine ring. Since the four regioisomeric furopyridines show almost the same σ1 affinity (Ki = 4.9–10 nM), a directed interaction of the pyridine N-atom with the receptor protein can be excluded. |
| Databáze: | OpenAIRE |
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