Synthesis,GluN2B affinity and selectivity of benzo[7]annulen-7-amines |
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| Affiliation: | 1. Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, 48149 Münster, Germany;2. NRW Graduate School of Chemistry, Wilhelm-Klemm Str. 10, 48149 Münster, Germany;3. Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino, 1, 62032 Camerino, Italy;4. Cells-in-Motion Cluster of Excellence (EXC 1003—CiM), University of Münster, Germany;1. Botswana Institute for Technology Research and Innovation, Private Bag 0082, Gaborone, Botswana;2. Department of Biological Sciences, University of Botswana, Private Bag 00704, Gaborone, Botswana;1. Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden;2. Department of Chemistry-BMC, Uppsala University, BMC, Box 576, SE-751 23 Uppsala, Sweden;3. Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden;4. The Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Uppsala University, A Node of the Chemical Biology Consortium Sweden (CBCS), Box 580, SE-751 23 Uppsala, Sweden;1. Department of Chemistry, National Taiwan University, Taipei 106, Taiwan;2. The Genomics Research Center, Academia Sinica, Taipei 115, Taiwan;3. National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112, Taiwan;1. Laboratory of Organic Chemistry, School of Chemical Engineering, National Technical University of Athens, Heroon Polytechniou 9, Zografou Campus, GR 15773 Athens, Greece;2. Aristotle University of Thessaloniki, School of Pharmacy, Department of Pharmaceutical Chemistry, 54124 Thessaloniki, Greece |
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| Abstract: | Due to their beneficial side effect profile, NMDA receptor antagonists interacting selectively with the allosteric ifenprodil binding site of the GluN2B subunit are of major interest for the treatment of neurological and neurodegenerative disorders. A series of benzo[7]annulen-7-amines 6 was designed by conformational restriction of ifenprodil (1). At first the benzo[7]annulen-7-one 11 was prepared in a three-step synthesis comprising of a double Knoevenagel condensation of phthalaldehyde (7) with dimethyl 3-oxoglutarate (8), hydrogenation of 9 and saponification/decarboxylation of 10. Reductive amination of the ketone 11 with primary amines and NaBH(OAc)3 led to the secondary amines 6a–d, cis-6h and trans-6i. The tertiary amines 6e–g were obtained by SN2-substitution of the nosylate 13. Although H-bond forming substituents in 2- and 5-position are missing, the amines 6 exhibit high affinity towards GluN2B containing NMDA receptors. A distance of four to five bond lengths between the basic amino moiety and the phenyl ring in the side chain appears to be optimal for high GluN2B affinity. The phenylcyclohexylamine cis-6h and the 4-benzylpiperidine 6g show the highest GluN2B affinities (Ki = 2.3 nM and 2.9 nM, respectively). With respect to selectivity against the PCP binding site, σ1 and σ2 receptors the phenylpiperazine 6f is the most promising GluN2B antagonist. |
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| Keywords: | NMDA receptor GluN2B antagonists Benzo[7]annulen-7-amines Structure affinity relationships Selectivity Conformational restriction |
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