Abstract
Conformationally restricted analogues of (+/-)-(Z)-2-aminomethyl-1-phenyl-N,N-diethylcyclopropanecarboxamide++ + [milnacipran, (+/-)-1] were designed on the basis of its characteristic cyclopropane structure and were synthesized enantioselectively to develop efficient NMDA receptor antagonists. Among these analogues, (1S,2R)-1-phenyl-2-[(R)-1-amino-2-propynyl]-N, N-diethylcyclopropanecarboxamide (2d) had one of the most potent affinities for the receptor, with a Ki value of 0.29 microM. The blockade of NMDA receptor channels expressed by Xenopus oocytes by 2d was investigated in detail, and 2d was identified as a new class of open channel blocker against this receptor.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antidepressive Agents / chemistry*
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Antidepressive Agents / metabolism
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Antidepressive Agents / pharmacology
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Cerebral Cortex / metabolism
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Cyclopropanes* / chemical synthesis
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Cyclopropanes* / chemistry*
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Cyclopropanes* / metabolism
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Cyclopropanes* / pharmacology
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Excitatory Amino Acid Antagonists* / chemical synthesis
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Excitatory Amino Acid Antagonists* / chemistry
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Excitatory Amino Acid Antagonists* / metabolism
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Excitatory Amino Acid Antagonists* / pharmacology
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Milnacipran
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Molecular Conformation
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Oocytes
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Patch-Clamp Techniques
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Rats
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
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Receptors, N-Methyl-D-Aspartate / biosynthesis
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Receptors, N-Methyl-D-Aspartate / metabolism
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Selective Serotonin Reuptake Inhibitors* / chemical synthesis
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Selective Serotonin Reuptake Inhibitors* / chemistry
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Selective Serotonin Reuptake Inhibitors* / metabolism
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Selective Serotonin Reuptake Inhibitors* / pharmacology
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Stereoisomerism
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Xenopus laevis
Substances
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1-phenyl-2-(1-amino-2-propynyl)-N,N-diethylcyclopropanecarboxamide
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Antidepressive Agents
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Cyclopropanes
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Excitatory Amino Acid Antagonists
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Receptors, N-Methyl-D-Aspartate
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Serotonin Uptake Inhibitors
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Milnacipran