title: Synthesis and σ receptor affinity of regioisomeric spirocyclic furopyridines.
abstract: 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.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms - Universität Münster, Corrensstraße 48, D-48149 Münster, Germany; Research Center for Materials Science and Department of Chemistry, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Miyata
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms - Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms - Universität Münster, Corrensstraße 48, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University Münster, Germany. Electronic address: wuensch@uni-muenster.de.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D003500:Cyclization; D006168:Guinea Pigs; D006860:Hydrogen Bonding; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D011725:Pyridines; D017480:Receptors, sigma; D013141:Spiro Compounds
keywords: Furopyridines; Regioisomers; Spirocyclic piperidines; Structure affinity relationships; σ(1) receptor ligands