Improved synthesis and in vitro/in vivo activities of natural product-inspired, artificial glutamate analogs.
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.
Oikawa
Masato
M
Graduate School of Nanobioscience, Yokohama City University, Yokohama 236-0027, Japan. moikawa@yokohama-cu.ac.jp
Ikoma
Minoru
M
Sasaki
Makoto
M
Gill
Martin B
MB
Swanson
Geoffrey T
GT
Shimamoto
Keiko
K
Sakai
Ryuichi
R
D000818:Animals; D001688:Biological Products / Q000737:chemistry; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D006571:Heterocyclic Compounds / Q000737:chemistry; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines; D011760:Pyrrolidinones; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001688:Biological Products; D006571:Heterocyclic Compounds; D010880:Piperidines; D011760:Pyrrolidinones; D018091:Receptors, AMPA; D018698:Glutamic Acid; C032727:piperidine
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