GluN2B‐Selective N‐Methyl‐d‐aspartate (NMDA) Receptor Antagonists Derived from 3‐Benzazepines: Synthesis and Pharmacological Evaluation of Benzo[7]annulen‐7‐amines |
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Authors: | Dr Andre Benner Alessandro Bonifazi Chikako Shirataki Louisa Temme Dr Dirk Schepmann Prof Wilma Quaglia Prof Osami Shoji Prof Yoshihito Watanabe Dr Constantin Daniliuc Prof?Dr Bernhard Wünsch |
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Affiliation: | 1. Institut für Pharmazeutische und Medizinische Chemie der Universit?t, Münster, Corrensstra?e 48, 48149 Münster (Germany);2. Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino (Italy);3. Department of Chemistry, Graduate School of Science, Nagoya University, Furo‐cho, Chikusa‐ku, Nagoya, 464‐8602 (Japan);4. Research Center for Materials Science, Nagoya University, Furo‐cho, Chikusa‐ku, 464‐8602 (Japan);5. Organisch‐chemisches Institut der Westf?lischen Wilhelms‐Universit?t, Münster, Corrensstra?e 40, 48149 Münster (Germany) |
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Abstract: | Given their high neuroprotective potential, ligands that block GluN2B‐containing N‐methyl‐D ‐aspartate (NMDA) receptors by interacting with the ifenprodil binding site located on the GluN2B subunit are of great interest for the treatment of various neuronal disorders. In this study, a novel class of GluN2B‐selective NMDA receptor antagonists with the benzo7]annulene scaffold was prepared and pharmacologically evaluated. The key intermediate, N‐(2‐methoxy‐5‐oxo‐6,7,8,9‐tetrahydro‐5H‐benzo7]annulen‐7‐yl)acetamide ( 11 ), was obtained by cyclization of 3‐acetamido‐5‐(3‐methoxyphenyl)pentanoic acid ( 10 b ). The final reaction steps comprise hydrolysis of the amide, reduction of the ketone, and reductive alkylation, leading to cis‐ and trans‐configured 7‐(ω‐phenylalkylamino)benzo7]annulen‐5‐ols. High GluN2B affinity was observed with cis‐configured γ‐amino alcohols substituted with a 3‐phenylpropyl moiety at the amino group. Removal of the benzylic hydroxy moiety led to the most potent GluN2B antagonists of this series: 2‐methoxy‐N‐(3‐phenylpropyl)‐6,7,8,9‐tetrahydro‐5H‐benzo7]annulen‐7‐amine ( 20 a , Ki=10 nM ) and 2‐methoxy‐N‐methyl‐N‐(3‐phenylpropyl)‐6,7,8,9‐tetrahydro‐5H‐benzo7]annulen‐7‐amine ( 23 a , Ki=7.9 nM ). The selectivity over related receptors (phencyclidine binding site of the NMDA receptor, σ1 and σ2 receptors) was recorded. In a functional assay measuring the cytoprotective activity of the benzo7]annulenamines, all tested compounds showed potent NMDA receptor antagonistic activity. Cytotoxicity induced via GluN2A subunit‐containing NMDA receptors was not inhibited by the new ligands. |
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Keywords: | benzo[7]annulenamines cytoprotective activity GluN2B NDMA receptors selectivity structure– affinity relationships |
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