2,3-Ethylene- and 2,3-trimethylene-bridged analogues of the group III metabotropic glutamate receptor ligand 2-amino-4-phosphonobutanoic acid

Rodney L Johnson; Kolluri S S P Rao

doi:10.1016/j.bmcl.2004.10.040

2,3-Ethylene- and 2,3-trimethylene-bridged analogues of the group III metabotropic glutamate receptor ligand 2-amino-4-phosphonobutanoic acid

Rodney L Johnson, Kolluri S S P Rao

Medicinal Chemistry

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

12 Scopus citations

Abstract

The racemic trans- and cis-isomers of 1-amino-2-phosphonomethyl- cyclobutanecarboxylic acid (5 and 6) and 1-amino-2-phosphonomethyl- cyclopentanecarboxylic acid (7 and 8) were synthesized as extensions of the mGluR4 agonists trans- and cis-1-amino-2-phosphonomethyl-cyclopropanecarboxylic acid (3 and 4). Although the methylene bridge in 3 and 4 allows for retention of affinity toward the mGluR4 receptor, increasing the bridging unit to the ethylene group as in 5 and 6 or to the trimethylene group as in 7 and 8 introduces sufficient steric hindrance to eliminate affinity for the mGluR4 receptor.

Original language	English (US)
Pages (from-to)	57-60
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	15
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2004.10.040
State	Published - Jan 3 2005

Bibliographical note

Funding Information:
This work was supported in part from a grant from NIH (NS35608) and a Development Grant in Drug Design from the Department of Medicinal Chemistry, University of Minnesota. The crystallographic analysis carried out by Neil R Brooks and Victor G. Young, Jr. of the University of Minnesota X-ray Crystallographic Laboratory is gratefully acknowledged. The authors thank Dr. James Monn and Renee Emkey of Eli Lilly and Company for arranging and conducting, respectively, the biological testing.

Keywords

AP4
Conformational analogues
mGluR4

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10.1016/j.bmcl.2004.10.040

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title = "2,3-Ethylene- and 2,3-trimethylene-bridged analogues of the group III metabotropic glutamate receptor ligand 2-amino-4-phosphonobutanoic acid",

abstract = "The racemic trans- and cis-isomers of 1-amino-2-phosphonomethyl- cyclobutanecarboxylic acid (5 and 6) and 1-amino-2-phosphonomethyl- cyclopentanecarboxylic acid (7 and 8) were synthesized as extensions of the mGluR4 agonists trans- and cis-1-amino-2-phosphonomethyl-cyclopropanecarboxylic acid (3 and 4). Although the methylene bridge in 3 and 4 allows for retention of affinity toward the mGluR4 receptor, increasing the bridging unit to the ethylene group as in 5 and 6 or to the trimethylene group as in 7 and 8 introduces sufficient steric hindrance to eliminate affinity for the mGluR4 receptor.",

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author = "Johnson, {Rodney L} and Rao, {Kolluri S S P}",

note = "Funding Information: This work was supported in part from a grant from NIH (NS35608) and a Development Grant in Drug Design from the Department of Medicinal Chemistry, University of Minnesota. The crystallographic analysis carried out by Neil R Brooks and Victor G. Young, Jr. of the University of Minnesota X-ray Crystallographic Laboratory is gratefully acknowledged. The authors thank Dr. James Monn and Renee Emkey of Eli Lilly and Company for arranging and conducting, respectively, the biological testing.",

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AU - Johnson, Rodney L

AU - Rao, Kolluri S S P

N1 - Funding Information: This work was supported in part from a grant from NIH (NS35608) and a Development Grant in Drug Design from the Department of Medicinal Chemistry, University of Minnesota. The crystallographic analysis carried out by Neil R Brooks and Victor G. Young, Jr. of the University of Minnesota X-ray Crystallographic Laboratory is gratefully acknowledged. The authors thank Dr. James Monn and Renee Emkey of Eli Lilly and Company for arranging and conducting, respectively, the biological testing.

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N2 - The racemic trans- and cis-isomers of 1-amino-2-phosphonomethyl- cyclobutanecarboxylic acid (5 and 6) and 1-amino-2-phosphonomethyl- cyclopentanecarboxylic acid (7 and 8) were synthesized as extensions of the mGluR4 agonists trans- and cis-1-amino-2-phosphonomethyl-cyclopropanecarboxylic acid (3 and 4). Although the methylene bridge in 3 and 4 allows for retention of affinity toward the mGluR4 receptor, increasing the bridging unit to the ethylene group as in 5 and 6 or to the trimethylene group as in 7 and 8 introduces sufficient steric hindrance to eliminate affinity for the mGluR4 receptor.

AB - The racemic trans- and cis-isomers of 1-amino-2-phosphonomethyl- cyclobutanecarboxylic acid (5 and 6) and 1-amino-2-phosphonomethyl- cyclopentanecarboxylic acid (7 and 8) were synthesized as extensions of the mGluR4 agonists trans- and cis-1-amino-2-phosphonomethyl-cyclopropanecarboxylic acid (3 and 4). Although the methylene bridge in 3 and 4 allows for retention of affinity toward the mGluR4 receptor, increasing the bridging unit to the ethylene group as in 5 and 6 or to the trimethylene group as in 7 and 8 introduces sufficient steric hindrance to eliminate affinity for the mGluR4 receptor.

KW - AP4

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KW - mGluR4

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2,3-Ethylene- and 2,3-trimethylene-bridged analogues of the group III metabotropic glutamate receptor ligand 2-amino-4-phosphonobutanoic acid

Abstract

Bibliographical note

Keywords

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