Synthesis and Bioactivity of a New Class of Rigid Glutamate Analogues. Modulators of the N-Methyl-D-aspartate Receptor

Alan P. Kozikowski; Werner Tuckmantel; Ian J. Reynolds; Jarda T. Wroblewski

doi:10.1021/jm00168a007

Synthesis and Bioactivity of a New Class of Rigid Glutamate Analogues. Modulators of the N-Methyl-D-aspartate Receptor

Alan P. Kozikowski, Werner Tuckmantel, Ian J. Reynolds, Jarda T. Wroblewski

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

A variety of derivatives of azetidine-2,4*dicarboxylic acid were synthesized and examined for their ability to stimulate ⁴⁵Ca²⁺ uptake in cultures of cerebellar granule cells. Of the compounds tested, the cis-azetidine-2,4-dicarboxylic acid (lOf) was found to be the most potent agent in potentiating glutamate, aspartate, or N-methyl-D-a9partate (NMDA) stimulated ⁴⁵Ca²⁺ uptake at the NMDA receptor. The mechanism of action of lOf was further investigated in [3H]MK-801 binding assays and [3H]GABA release from cultured embryonic rat forebrain neurons. All of the results from the functional studies of azetidine lOf are consistent with a selectivity of action at the NMDA receptor. Moreover, azetidine lOf appears to exhibit a dual type of action, behaving as a glutamate-like agonist at higher concentrations and as a positive modulator at concentrations below 50µM.

Original language	English (US)
Pages (from-to)	1561-1571
Number of pages	11
Journal	Journal of medicinal chemistry
Volume	33
Issue number	6
DOIs	https://doi.org/10.1021/jm00168a007
State	Published - 1990

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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title = "Synthesis and Bioactivity of a New Class of Rigid Glutamate Analogues. Modulators of the N-Methyl-D-aspartate Receptor",

abstract = "A variety of derivatives of azetidine-2,4*dicarboxylic acid were synthesized and examined for their ability to stimulate 45Ca2+ uptake in cultures of cerebellar granule cells. Of the compounds tested, the cis-azetidine-2,4-dicarboxylic acid (lOf) was found to be the most potent agent in potentiating glutamate, aspartate, or N-methyl-D-a9partate (NMDA) stimulated 45Ca2+ uptake at the NMDA receptor. The mechanism of action of lOf was further investigated in [3H]MK-801 binding assays and [3H]GABA release from cultured embryonic rat forebrain neurons. All of the results from the functional studies of azetidine lOf are consistent with a selectivity of action at the NMDA receptor. Moreover, azetidine lOf appears to exhibit a dual type of action, behaving as a glutamate-like agonist at higher concentrations and as a positive modulator at concentrations below 50µM.",

author = "Kozikowski, {Alan P.} and Werner Tuckmantel and Reynolds, {Ian J.} and Wroblewski, {Jarda T.}",

year = "1990",

doi = "10.1021/jm00168a007",

language = "English (US)",

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pages = "1561--1571",

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T1 - Synthesis and Bioactivity of a New Class of Rigid Glutamate Analogues. Modulators of the N-Methyl-D-aspartate Receptor

AU - Kozikowski, Alan P.

AU - Tuckmantel, Werner

AU - Reynolds, Ian J.

AU - Wroblewski, Jarda T.

PY - 1990

Y1 - 1990

N2 - A variety of derivatives of azetidine-2,4*dicarboxylic acid were synthesized and examined for their ability to stimulate 45Ca2+ uptake in cultures of cerebellar granule cells. Of the compounds tested, the cis-azetidine-2,4-dicarboxylic acid (lOf) was found to be the most potent agent in potentiating glutamate, aspartate, or N-methyl-D-a9partate (NMDA) stimulated 45Ca2+ uptake at the NMDA receptor. The mechanism of action of lOf was further investigated in [3H]MK-801 binding assays and [3H]GABA release from cultured embryonic rat forebrain neurons. All of the results from the functional studies of azetidine lOf are consistent with a selectivity of action at the NMDA receptor. Moreover, azetidine lOf appears to exhibit a dual type of action, behaving as a glutamate-like agonist at higher concentrations and as a positive modulator at concentrations below 50µM.

AB - A variety of derivatives of azetidine-2,4*dicarboxylic acid were synthesized and examined for their ability to stimulate 45Ca2+ uptake in cultures of cerebellar granule cells. Of the compounds tested, the cis-azetidine-2,4-dicarboxylic acid (lOf) was found to be the most potent agent in potentiating glutamate, aspartate, or N-methyl-D-a9partate (NMDA) stimulated 45Ca2+ uptake at the NMDA receptor. The mechanism of action of lOf was further investigated in [3H]MK-801 binding assays and [3H]GABA release from cultured embryonic rat forebrain neurons. All of the results from the functional studies of azetidine lOf are consistent with a selectivity of action at the NMDA receptor. Moreover, azetidine lOf appears to exhibit a dual type of action, behaving as a glutamate-like agonist at higher concentrations and as a positive modulator at concentrations below 50µM.

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