Synthesis and pharmacology of N-alkylated derivatives of the excitotoxin ibotenic acid

U Madsen; M A Dumpis; Hans Bräuner-Osborne; L B Piotrovsky

Synthesis and pharmacology of N-alkylated derivatives of the excitotoxin ibotenic acid

U Madsen, M A Dumpis, Hans Bräuner-Osborne, L B Piotrovsky

10 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Bioorganic & Medicinal Chemistry Letters
Vol/bind	8
Udgave nummer	12
Sider (fra-til)	1563-8
ISSN	0960-894X
Status	Udgivet - 16 jun. 1998

Citationsformater

@article{a71d0c896c4d482484f84146919faf99,

title = "Synthesis and pharmacology of N-alkylated derivatives of the excitotoxin ibotenic acid",

abstract = "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.",

keywords = "Animals, CHO Cells, Cerebral Cortex, Cricetinae, Excitatory Amino Acid Agonists, Ibotenic Acid, Molecular Structure, Rats, Receptors, N-Methyl-D-Aspartate, Structure-Activity Relationship",

author = "U Madsen and Dumpis, {M A} and Hans Br{\"a}uner-Osborne and Piotrovsky, {L B}",

year = "1998",

month = jun,

day = "16",

language = "English",

volume = "8",

pages = "1563--8",

journal = "Bioorganic & Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Pergamon Press",

number = "12",

}

TY - JOUR

T1 - Synthesis and pharmacology of N-alkylated derivatives of the excitotoxin ibotenic acid

AU - Madsen, U

AU - Dumpis, M A

AU - Bräuner-Osborne, Hans

AU - Piotrovsky, L B

PY - 1998/6/16

Y1 - 1998/6/16

N2 - 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.

AB - 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.

KW - Animals

KW - CHO Cells

KW - Cerebral Cortex

KW - Cricetinae

KW - Excitatory Amino Acid Agonists

KW - Ibotenic Acid

KW - Molecular Structure

KW - Rats

KW - Receptors, N-Methyl-D-Aspartate

KW - Structure-Activity Relationship

M3 - Journal article

C2 - 9873391

SN - 0960-894X

VL - 8

SP - 1563

EP - 1568

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 12

ER -

Synthesis and pharmacology of N-alkylated derivatives of the excitotoxin ibotenic acid

Abstract

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