title: Pyridine analogues of spirocyclic σ₁ receptor ligands.
abstract: Spirocyclic benzopyrans 2 interact with high affinity and selectivity with σ₁ receptors. Bioisosteric replacement of the benzene ring of the benzopyran substructure with the electron rich thiophene ring (3) led to increased σ₁ affinity. Herein the synthesis and pharmacological evaluation of electron deficient pyridine bioisosteres 4 are reported. Homologation of the aldehyde 6 to afford the pyridylacetaldehyde derivative 8 was performed by a Wittig reaction. Bromine lithium exchange of the bromopyridine 8, addition to 1-benzylpiperidin-4-one and cyclization led to the spirocyclic pyrranopyridine 10. Hydrogenolytic removal of the N-benzyl moiety of 10 provided the secondary amine 11, which allowed the introduction of various N-substituents (12a-d). Cyclization of the hydroxy acetal 9 with HCl led to various modifications of the substituent in 3'-position. Generally the σ₁ affinity of the pyridine derivatives is reduced compared with those of the benzene and thiophene derivatives 2 and 3. However, the relationships between the structure and the σ₁ affinity follow the same rules as for the benzene and thiophene derivatives. The most promising σ₁ ligand within this class of compounds is the pyranopyridine 15 with a double bond in the pyran ring revealing a Ki-value of 4.6 nM and a very high selectivity (>217-fold) over the σ₂ subtype.
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: Guido
authors.initials: G
authors.lastname: Möller
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; D001921:Brain / Q000378:metabolism; D003500:Cyclization; D006168:Guinea Pigs; D008024:Ligands; D008099:Liver / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011714:Pyrans / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017480:Receptors, sigma / Q000737:chemistry* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D020033:Protein Isoforms; D011714:Pyrans; D011725:Pyridines; D017480:Receptors, sigma; D013141:Spiro Compounds; C023666:pyridine
keywords: Electron density; Pyranopyridines; Spirocyclic piperidines; Structure affinity relationships; σ(1) Receptor ligands