Synthesis and pharmacology of N-alkylated derivatives of the excitotoxin ibotenic acid.
Three amino-alkylated derivatives of the naturally occurring excitatory amino acid (EAA) receptor agonist ibotenic acid (Ibo) have been synthesized and tested pharmacologically. N-Methyl-Ibo (1a) and N-ethyl-Ibo (1b) were shown to be agonists at NMDA receptors (EC50 = 140 and 320 microM, respectively), though with activities considerably lower than Ibo (EC50 = 9.6 microM). N-Benzyl-Ibo (1c) was inactive at ionotropic EAA receptors and all three compounds were, in contrast to Ibo, inactive at metabotropic EAA receptors. Molecular mechanics calculations have been performed on Ibo, 1a-c and the potent NMDA agonist 2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid (AMAA) in order to elucidate the observed structure-activity data.
Madsen
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Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen, Denmark. ulf@medchem.dfh.dk
Dumpis
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Bräuner-Osborne
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Piotrovsky
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D000818:Animals; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D018690:Excitatory Amino Acid Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007051:Ibotenic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015394:Molecular Structure; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D013329:Structure-Activity Relationship
D018690:Excitatory Amino Acid Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D007051:Ibotenic Acid