Heterocyclic excitatory amino acids. Synthesis and biological activity of novel analogues of AMPA.
The novel acidic amino acids 6a-c, 7, and 8 have been synthesized via 1,3-dipolar cycloadditions, using nitrile oxides and alkynes. The prepared compounds are heterocyclic analogues of glutamic acid with differing chain lengths. One of these compounds, (RS)-2-amino-3-(3-carboxy-5-methyl-4- isoxazolyl)propionic acid (ACPA, 8), was shown in [3H]AMPA binding studies to be more active than AMPA itself (IC50 = 20 nM compared to IC50 = 79 nM for AMPA). No affinity for NMDA receptors (NMDA-sensitive [3H]glutamic acid binding) was found, and only weak affinity in [3H]kainic acid binding (IC50 = 6.3 microM) was detected. The excitatory activity in rat cortical wedge also showed that ACPA was more potent than AMPA (EC50 = 1.0 microM compared to EC50 = 3.5 microM for AMPA). The depolarizing effect of ACPA could be fully antagonized by the selective non-NMDA antagonist 6-cyano-7-nitro-quinoxazoline-2,3-dione (CNQX), but was unaffected by the selective NMDA antagonist D-2-amino-5-phosphonovaleric acid (AP5).
Institute of Organic Chemistry, Syntex Research, Palo Alto, California 94304.
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Madsen
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Wong
D000596:Amino Acids / Q000138:chemical synthesis*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004594:Electrophysiology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis*; D007051:Ibotenic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface / Q000378:metabolism; D013329:Structure-Activity Relationship; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D000596:Amino Acids; D006571:Heterocyclic Compounds; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface; D007051:Ibotenic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid