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.
Bibliographical noteFunding 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.
Copyright 2012 Elsevier B.V., All rights reserved.
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