Improved synthesis and in vitro/in vivo activities of natural product-inspired,artificial glutamate analogs |
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Authors: | Masato Oikawa Minoru Ikoma Makoto Sasaki Martin B. Gill Geoffrey T. Swanson Keiko Shimamoto Ryuichi Sakai |
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Affiliation: | 1. Graduate School of Nanobioscience, Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan;2. Graduate School of Life Sciences, Tohoku University, Aoba-ku, Sendai 981-8555, Japan;3. Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL 60611, USA;4. Suntory Institute for Bioorganic Research (SUNBOR), Mishima-gun, Osaka 618-8503, Japan;5. Graduate School of Fisheries Sciences, Hokkaido University, Minato-cho, Hakodate 041-8611, Japan |
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Abstract: | Here, we report our second-generation synthesis of 12 artificial glutamate analogs, starting from heterotricycle intermediates 3a–3d, readily prepared in three steps including tandem Ugi/Diels-Alder reactions. The new synthesis employs imidate intermediates for the deoxygenation of pyrrolidones (10a–10d to 6a–6d), and each advanced intermediate 6a–6d was diversified into three glutamate analogs (1a–1d, 5a–5d, 7a–7d) in 1–2 steps.In vitro electrophysiological assays revealed that the new piperidine-type analog 7c alters neuronal function with lower potency than 1a. Conversely, intracranial injection of 7c into mice produced a greater degree of hypoactivity than 1a. Our recent investigation has revealed that this series of compounds antagonizes AMPA-type glutamate receptor-mediated currents in a subtype selective manner. The more efficient syntheses of this novel set of neuroactive molecules will facilitate their pharmacological characterization. |
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