Pyridine analogues of spirocyclic σ1 receptor ligands |
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| Institution: | 1. Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany;2. Research Center for Materials Science and Department of Chemistry, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan;3. Cells-in-Motion Cluster of Excellence (EXC 1003—CiM), University Münster, Germany;1. Unidad de Arritmias, Servicio de Cardiología, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, España;2. Servicio de Cardiología, Hospital Universitario Quirón, Universidad Europea de Madrid, Madrid, España;3. Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, España;4. Unidad de Imagen Cardiaca, Servicio de Cardiología, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, España;1. Research Center for Solid State Physics and Materials, School of Mathematics and Physics, Suzhou University of Science and Technology, Suzhou 215009, PR China;2. Department of Applied Physics and Materials Research Center, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China;1. G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences, Akademicheskaya, 1, 153045 Ivanovo, Russia;2. Research Institute of Macroheterocycles of Ivanovo State University of Chemistry and Technology, 153000 Ivanovo, Russia;1. CEA, DEN, DTCD/SPDE/LPSD – Marcoule, F-30207 Bagnols-sur-Cèze, France;2. Laboratoire Charles Coulomb, Université Montpellier 2, 34095 Montpellier cedex 05, France;3. Institut Européen des Membranes, Université Montpellier 2, 34095 Montpellier cedex 05, France |
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| 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. |
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| Keywords: | Spirocyclic piperidines Electron density Pyranopyridines Structure affinity relationships |
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